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http://www.ncbi.nlm.nih.gov/pubmed/12209078 | 1. J Allergy Clin Immunol. 2002 Sep;110(3):341-8. doi: 10.1067/mai.2002.126811.
Anaphylaxis: a review of causes and mechanisms.
Kemp SF(1), Lockey RF.
Author information:
(1)Division of Allergy and Immunology, Department of Medicine, The University of
Mississippi Medical Center, Jackson, USA.
Anaphylaxis is a life-threatening syndrome resulting from the sudden release of
mast cell- and basophil-derived mediators into the circulation. Foods and
medications cause most anaphylaxis for which a cause can be identified, but
virtually any agent capable of directly or indirectly activating mast cells or
basophils can cause this syndrome. This review discusses the pathophysiologic
mechanisms of anaphylaxis, its causes, and its treatment.
DOI: 10.1067/mai.2002.126811
PMID: 12209078 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15025396 | 1. Novartis Found Symp. 2004;257:133-49; discussion 149-60, 276-85.
The human heart as a shock organ in anaphylaxis.
Marone G(1), Bova M, Detoraki A, Onorati AM, Rossi FW, Spadaro G.
Author information:
(1)Department of Clinical Immunology and Allergy, University of Naples Federico
II, School of Medicine, Via S. Pansini 5, 80131 Naples, Italy.
Human mast cells, by elaborating vasoactive mediators and cytokines, are the
primary effector cells of anaphylaxis. A body of evidence implicates human heart
mast cells (HHMCs) in anaphylaxis. These cells have been identified
perivascularly, in dose proximity to myocytes and in the arterial intima in
human heart tissue. The membrane surface of mast cells from human heart tissue
of patients undergoing cardiac transplantation expresses the high affinity
receptors for IgE (FcepsilonRI) and C5a receptors. Activation of HHMCs in vitro
with anti-IgE or anti-FcepsilonRI induced the release of preformed mediators
(histamine, tryptase and chymase) and the de novo synthesis of LTC4
(approximately equal to 18 ng/10(6) cells) and PGD2 (approximately equal to 18
ng/10(6) cells). Complement activation and anaphylatoxin formation occur during
anaphylaxis in human. C5a caused rapid release of histamine and tryptase from
HHMCs. These cells are activated in vitro by therapeutic (general anaesthetics,
protamine, etc.) and diagnostic agents (radio contrast media, etc.) that may
cause non-IgE-mediated anaphylactic reactions. Administration of low
concentrations of histamine and cysteinyl leukotrienes in subjects undergoing
diagnostic catheterization caused significant systemic and coronary haemodynamic
effects. Taken together, these results indicate that the human heart can be both
the site and the target of anaphylactic reactions.
PMID: 15025396 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35080312 | 1. Pediatr Allergy Immunol. 2022 Jan;33 Suppl 27:52-53. doi: 10.1111/pai.13629.
Update on idiopathic anaphylaxis.
Calvani M(1).
Author information:
(1)Pediatric Complex Operative Unit, "S. Camillo-Forlanini" Hospital, Rome,
Italy.
Idiopathic anaphylaxis (AI) refers to anaphylaxis without a recognizable cause
after a comprehensive allergic workup. The diagnostic approach usually includes
an accurate clinical history aimed at excluding both the most and the less
frequent causes of anaphylaxis and all pathologies that may resemble
anaphylaxis. AI is more common in adults than in children. The epidemiology of
AI has been reduced in recent years, probably to increase knowledge and discover
new clinical entities, such as the α-gal anaphylaxis. Anaphylaxis results from
the massive activation of the mast cells (MCs). Thus, it is also necessary to
exclude MC disorders, such as mastocytosis and mast cell activation syndrome,
and α-tryptasemia, which may manifest with IA symptoms.
© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons
Ltd.
DOI: 10.1111/pai.13629
PMID: 35080312 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15025392 | 1. Novartis Found Symp. 2004;257:65-74; discussion 74-9, 98-100, 276-85.
Effector cells of anaphylaxis: mast cells and basophils.
Schwartz LB(1).
Author information:
(1)Division of Rheumatology, Allergy and Immunology, Virginia Commonwealth
University, PO Box 980263, Richmond, VA 23298, USA.
Systemic anaphylaxis arises when mast cells, possibly along with other cell
types, are provoked to secrete mediators that evoke a systemic response. Mast
cells in perivascular, respiratory, gastrointestinal and cutaneous tissues are
likely involved, regardless of whether IgE or non-IgE-dependent pathways are
invoked. Alpha/beta tryptases are selectively and abundantly produced by mast
cells. Tryptase levels in the circulation provide a precise indicator of mast
cell involvement. Mature beta tryptase is stored in secretory granules and is
released when the cells are activated to degranulate, as occurs in anaphylaxis.
Alpha/beta pro/pro' tryptases are spontaneously secreted by mast cells.
Consequently, mature tryptase levels in serum (normally 1 ng/ml) are elevated in
systemic anaphylaxis. Total tryptase levels (mature plus precursor forms),
normally 1-15 ng/ml in baseline serum samples, are elevated in patients with
systemic mastocytosis (> 20 ng/ml), a disease that also predisposes one to
anaphylactic reactions. The assessment of basophils in systemic anaphylactic
reactions has been problematic, because an assay for a specific releasable
marker from this cell type has not been developed. Nevertheless, in cases of
anaphylaxis in which elevations of histamine, but not tryptase, have been
detected, it is enticing to speculate that basophil-dependent anaphylaxis may
have occurred.
PMID: 15025392 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22794697 | 1. Allergy Asthma Proc. 2012 May-Jun;33 Suppl 1:80-83. doi:
10.2500/aap.2012.33.3557.
Chapter 24: Anaphylaxis.
Greenberger PA, Ditto AM.
Anaphylaxis is a sudden-onset, immediate reaction that implies a risk of death.
Think of a "rule of 2's" for anaphylaxis implying that reactions usually begin
within 2 minutes to 2 hours after injection, infusion, ingestion, contact, or
inhalation. Fatalities can be from asphyxiation from laryngeal or oropharyngeal
swelling, collapse from hypotensive shock, cardiac arrest, or acute severe
bronchoconstriction causing respiratory failure and arrest. When there is
activation of mast cells and basophils in anaphylaxis, chemical mediators are
detectable. The preformed mediators from mast cells include histamine, tryptase,
carboxypeptidase A, and proteoglycans (heparin and chondroitin sulfates). Newly
synthesized mediators include prostaglandin D(2), leukotriene D(4), and
platelet-activating factor. Crucial actions of the mediators include an abrupt
increase in vascular permeability, vascular smooth muscle relaxation, and
bronchial smooth muscle contraction. Anaphylaxis can be classified into
immunologic, nonimmunologic, or idiopathic based on the associated mechanism.
For example, immunologic causes of anaphylaxis are those mediated by IgE
antibodies acting through the FcεR I (foods, insect venom, and beta-lactam
antibiotics) whereas non-IgE immunologic anaphylaxis is mediated without
presence of antiallergen IgE antibodies or via FcεRI activation (radiographic
contrast material). Nonimmunologic anaphylaxis involves mast cell mediator
release such as occurs with exercise, cold temperature exposure, or from
medications such as opioids or vancomycin. Idiopathic anaphylaxis involves mast
cell activation (acutely elevated urine histamine or serum tryptase) and
activated lymphocytes. Because anaphylaxis is a medical emergency, the drug of
choice is epinephrine, not H(1)-receptor antagonists.
DOI: 10.2500/aap.2012.33.3557
PMID: 22794697 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24586553 | 1. PLoS One. 2014 Feb 19;9(2):e89148. doi: 10.1371/journal.pone.0089148.
eCollection 2014.
Angiopoietin1 inhibits mast cell activation and protects against anaphylaxis.
Yao JH(1), Cui M(2), Li MT(1), Liu YN(1), He QH(1), Xiao JJ(1), Bai Y(1).
Author information:
(1)Department of Cell Biology, School of Basic Medical Sciences, Peking
University Health Science Center, Beijing, China.
(2)Department of Cardiology, Peking University Third Hospital, Beijing, China.
Since morbidity and mortality rates of anaphylaxis diseases have been increasing
year by year, how to prevent and manage these diseases effectively has become an
important issue. Mast cells play a central regulatory role in allergic diseases.
Angiopoietin1 (Ang-1) exhibits anti-inflammatory properties by inhibiting
vascular permeability, leukocyte migration and cytokine production. However,
Ang-1's function in mast cell activation and anaphylaxis diseases is unknown.
The results of our study suggest that Ang-1 decreased lipopolysaccharide
(LPS)-induced pro-inflammatory cytokines production of mast cells by suppressing
IκB phosphorylation and NF-κB nuclear translocation. Ang-1 also strongly
inhibited compound 48/80 induced and FcεRI-mediated mast cells degranulation by
decreasing intracellular calcium levels in vitro. In vivo lentivirus-mediated
delivery of Ang-1 in mice exhibited alleviated leakage in IgE-dependent passive
cutaneous anaphylaxis (PCA). Furthermore, exogenous Ang-1 intervention treatment
prevented mice from compound 48/80-induced mesentery mast cell degranulation,
attenuated increases in pro-inflammatory cytokines, relieved lung injury, and
improved survival in anaphylaxis shock. The results of our study reveal, for the
first time, the important role of Ang-1 in the activation of mast cells, and
identify a therapeutic effect of Ang-1 on anaphylaxis diseases.
DOI: 10.1371/journal.pone.0089148
PMCID: PMC3929638
PMID: 24586553 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/20526344 | 1. Nat Immunol. 2010 Jul;11(7):601-7. doi: 10.1038/ni.1886. Epub 2010 Jun 6.
An immunoglobulin-like receptor, Allergin-1, inhibits immunoglobulin E-mediated
immediate hypersensitivity reactions.
Hitomi K(1), Tahara-Hanaoka S, Someya S, Fujiki A, Tada H, Sugiyama T, Shibayama
S, Shibuya K, Shibuya A.
Author information:
(1)Department of Immunology, Institute of Basic Medical Sciences, Graduate
School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Anaphylaxis is a life-threatening immediate hypersensitivity reaction triggered
by antigen capture by immunoglobulin E (IgE) bound to the high-affinity IgE
receptor (FcvarepsilonRI) on mast cells. However, the regulatory mechanism of
mast cell activation is not completely understood. Here we identify an
immunoglobulin-like receptor, Allergin-1, that contains an immunoreceptor
tyrosine-based inhibitory motif (ITIM)-like domain, and show it was
preferentially expressed on mast cells. Mouse Allergin-1 recruited the tyrosine
phosphatases SHP-1 and SHP-2 and the inositol phosphatase SHIP. Coligation of
Allergin-1 and FcvarepsilonRI suppressed IgE-mediated degranulation of bone
marrow-derived cultured mast cells. Moreover, mice deficient in Allergin-1
developed enhanced passive systemic and cutaneous anaphylaxis. Thus, Allergin-1
suppresses IgE-mediated, mast cell-dependent anaphylaxis in mice.
DOI: 10.1038/ni.1886
PMID: 20526344 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34867939 | 1. Front Immunol. 2021 Nov 19;12:688930. doi: 10.3389/fimmu.2021.688930.
eCollection 2021.
Antibody or Anybody? Considering the Role of MRGPRX2 in Acute Drug-Induced
Anaphylaxis and as a Therapeutic Target.
Mackay GA(1), Fernandopulle NA(1), Ding J(1), McComish J(2), Soeding PF(1)(3).
Author information:
(1)Department of Biochemistry and Pharmacology, The University of Melbourne,
Parkville, VIC, Australia.
(2)Department of Clinical Immunology and Allergy, The Royal Melbourne Hospital,
Parkville, VIC, Australia.
(3)Department of Anaesthesia and Pain Medicine, The Royal Melbourne Hospital,
Parkville, VIC, Australia.
Acute anaphylaxis to small molecule drugs is largely considered to be
antibody-mediated with immunogloblin E (IgE) and mast cell activation being key.
More recently, a role for drug-reactive immunoglobulin G (IgG) with neutrophil
activation has also been suggested, at least in reactions to neuromuscular
blocking agents (NMBAs). However, the mast cell receptor MRGPRX2 has also been
highlighted as a possible triggering mechanism in acute anaphylaxis to many
clinically used drugs. Significantly, MRGPRX2 activation is not dependent upon
the presence of drug-recognising antibody. Given the reasonable assumption that
MRGPRX2 is expressed in all individuals, the corollary of this is that in
theory, anybody could respond detrimentally to triggering drugs (recently
suggested to be around 20% of a drug-like compound library). But this clearly is
not the case, as the incidence of acute drug-induced anaphylaxis is very low. In
this mini-review we consider antibody-dependent and -independent mechanisms of
mast cell activation by small molecule drugs with a focus on the MRGPRX2
pathway. Moreover, as a juxtaposition to these adverse drug actions, we consider
how increased understanding of the role of MRGPRX2 in anaphylaxis is important
for future drug development and can complement exploration of this receptor as a
drug target in broader clinical settings.
Copyright © 2021 Mackay, Fernandopulle, Ding, McComish and Soeding.
DOI: 10.3389/fimmu.2021.688930
PMCID: PMC8639860
PMID: 34867939 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33097573 | 1. J Immunol. 2020 Dec 1;205(11):2959-2967. doi: 10.4049/jimmunol.2000149. Epub
2020 Oct 23.
A Rapid Shift from Chronic Hyperoxia to Normoxia Induces Systemic Anaphylaxis
via Transient Receptor Potential Ankyrin 1 Channels on Mast Cells.
Matsuda K(1), Arkwright PD(2), Mori Y(3), Oikawa MA(4), Muko R(5), Tanaka
A(1)(5), Matsuda H(6).
Author information:
(1)Laboratory of Comparative Animal Medicine, Division of Animal Life Science,
Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo
183-8509, Japan.
(2)Lydia Becker Institute of Immunity and Inflammation, University of
Manchester, Manchester M13 9WL, United Kingdom.
(3)Department of Synthetic Chemistry and Biological Chemistry, Graduate School
of Engineering, Kyoto University, Kyoto 615-8510, Japan.
(4)Diagnostic and Research Laboratory, Equine Veterinary Medical Center, Doha,
Qatar; and.
(5)Cooperative Major in Advanced Health Science, Graduate School of
Bio-Applications and System Engineering, Tokyo University of Agriculture and
Technology, Tokyo 183-8509, Japan.
(6)Laboratory of Comparative Animal Medicine, Division of Animal Life Science,
Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo
183-8509, Japan; [email protected].
Extensive activation of mast cells is the major switch that triggers systemic
anaphylaxis, resulting in the subsequent release of anaphylactic mediators into
circulation. We previously demonstrated that rapid changes in oxygen tension
lead to mast cell degranulation, and the released tryptase triggers retinal
angiogenesis in a murine oxygen-induced retinopathy model. However, whether a
rapid shift from hyperoxia to normoxia (relative hypoxic stress) is a risk
factor for systemic anaphylaxis remains unknown. In this study, we demonstrated
that the relative hypoxia stress induces systemic mast cell activation via
transient receptor potential ankyrin 1 (TRPA1) channels, which immediately leads
to hypothermia and increased vascular permeability in adult mice. Although mast
cell-deficient or TRPA1-deficient mice did not exhibit anaphylactic symptoms
following a rapid sift to normoxia, preinjection with bone marrow-derived
cultured mast cells (BMCMCs) derived from wild-type TRPA1-expressing mice
restored anaphylactic responses. In addition, we found that the rapid reductions
in oxygen tension in a culture atmosphere triggered the degranulation of BMCMCs
derived from wild-type TRPA1-expressing mice but not that of BMCMCs derived from
TRPA1-deficient mice. In human LAD2 mast cells, the relative hypoxic stress led
to the degranulation, which was suppressed by the addition of a TRPA1 inhibitor.
Gradual reductions from hyperoxia to normoxia led to no anaphylactic symptoms.
Our results demonstrated that TRPA1-triggered mast cell degranulation is a novel
pathway that induces anaphylactic shock without Ag-Ab reactions. These findings
introduce a potential role for oxygen in inducing mast cell-dependent
anaphylaxis and highlight the need to reconsider chronic pure oxygen therapy for
anoxic diseases.
Copyright © 2020 by The American Association of Immunologists, Inc.
DOI: 10.4049/jimmunol.2000149
PMID: 33097573 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27906487 | 1. Clin Exp Allergy. 2017 Mar;47(3):361-370. doi: 10.1111/cea.12868. Epub 2017
Jan 13.
Neutrophil activation during acute human anaphylaxis: analysis of MPO and
sCD62L.
Francis A(1)(2), Bosio E(1)(2), Stone SF(1)(2), Fatovich DM(1)(2)(3), Arendts
G(1)(2)(3)(4), Nagree Y(1)(4)(5), Macdonald SP(1)(2)(3)(6), Mitenko H(1)(7),
Rajee M(1)(8), Burrows S(9), Brown SG(1)(2)(3)(10).
Author information:
(1)Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute
of Medical Research, Perth, WA, Australia.
(2)Discipline of Emergency Medicine, School of Primary, Aboriginal and Rural
Health Care, University of Western Australia, Crawley, WA, Australia.
(3)Emergency Department, Royal Perth Hospital, Perth, WA, Australia.
(4)Emergency Department, Fiona Stanley Hospital, Murdoch, WA, Australia.
(5)Emergency Department, Fremantle Hospital, Fremantle, WA, Australia.
(6)Emergency Department, Armadale Kelmscott Memorial Hospital, Mount Nasura, WA,
Australia.
(7)Emergency Department, South West Health Campus, Bunbury, WA, Australia.
(8)Emergency Department, Austin Hospital, Heidelberg, VIC, Australia.
(9)School of Medicine & Pharmacology, University of Western Australia, Perth,
WA, Australia.
(10)Emergency Department, Royal Hobart Hospital, Hobart, TAS, Australia.
BACKGROUND: The mechanisms involved in the amplification of the mast cell
response during anaphylaxis are unclear. Mouse models of anaphylaxis demonstrate
the critical involvement of neutrophils. These innate immune cells are highly
abundant in peripheral blood and can be rapidly activated to trigger both local
and systemic inflammation.
OBJECTIVE: To investigate neutrophil activation in peripheral blood during acute
human anaphylaxis.
METHODS: Patients presenting to the emergency department with anaphylaxis
underwent blood sampling upon enrolment and at up to three subsequent
time-points. Traditional anaphylaxis biomarkers, histamine and mast cell
tryptase, were measured by ELISA and ImmunoCAP, respectively. Plasma
myeloperoxidase concentrations were measured by ELISA, serum soluble CD62L
concentrations by cytometric bead array, and both compared to healthy controls.
RESULTS: In 72 patients, 37 (51%) had severe anaphylaxis, 33 (60%) were
histamine positive, and 47 (70%) were mast cell tryptase positive. At enrolment,
myeloperoxidase concentrations were 2.9- (95% CI: 1.3, 6.5) and 5.0- (95% CI:
2.4, 10.5) fold higher in moderate and severe patients, respectively, compared
with healthy controls, and remained stable over the first 5 h following symptom
onset. At enrolment, soluble CD62L was 29% (95% CI: 19, 38) and 31% (95% CI: 22,
40) lower in moderate and severe patients, respectively, than healthy controls,
and was stable over the first 5 h. There were no associations between
myeloperoxidase or soluble CD62L concentrations and either histamine or mast
cell tryptase concentrations.
CONCLUSIONS AND CLINICAL RELEVANCE: These results provide compelling evidence
for the involvement of neutrophils during acute human anaphylaxis, suggesting
they are activated early in the reaction, regardless of mast cell activation.
This important finding increases our understanding of the basic mechanisms of
anaphylaxis, a necessary precursor to improving treatment and prevention.
© 2016 John Wiley & Sons Ltd.
DOI: 10.1111/cea.12868
PMID: 27906487 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2661436 | 1. Indian J Physiol Pharmacol. 1989 Jan-Mar;33(1):47-52.
Immunopharmacological studies on Picrorhiza kurroa Royle ex Benth. Part VI:
Effect on anaphylactic activation events in rat peritoneal mast cells.
Pandey BL(1), Das PK, Gambhir SS.
Author information:
(1)Department of Pharmacology, Banaras Hindu University, Varanasi.
Mechanism of inhibition of mast cell anaphylaxis by P. kurroa-extract (PK)
treatment in rats was investigated. Mast cell-IgE binding, assessed from
induction of passive sensitization, was not affected. Calcium-independent early
activation events in mast cell anaphylaxis indicated on inhibitory influence of
PK-treatment. Inhibition of membrane-protease release by PK-treatment was
suggested by study of gastric secretion and exhibition of saturable synergism
with Di-isopropyl fluoro phosphate on inhibition of anaphylactic degranulation.
pH-independence of mast cell stabilizing effect negates any PK-influence on
phospholipid transmethylation. The results complement findings of earlier
studies on indirect effects of PK through alteration of membrane
structure/function.
PMID: 2661436 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24948367 | 1. J Allergy Clin Immunol. 2014 Sep;134(3):714-721.e7. doi:
10.1016/j.jaci.2014.05.001. Epub 2014 Jun 17.
ERK1/2 antagonize AMPK-dependent regulation of FcεRI-mediated mast cell
activation and anaphylaxis.
Hwang SL(1), Lu Y(2), Li X(1), Kim YD(1), Cho YS(3), Jahng Y(1), Son JK(1), Lee
YJ(4), Kang W(5), Taketomi Y(6), Murakami M(6), Moon TC(7), Chang HW(8).
Author information:
(1)College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
(2)College of Pharmacy, Yeungnam University, Gyeongsan, Korea; School of
Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
(3)Department of Allergy and Clinical Immunology, Asan Medical Center, College
of Medicine, Ulsan University, Seoul, Korea.
(4)Department of Pharmacology, School of Medicine, Catholic University of Daegu,
Daegu, Korea.
(5)College of Pharmacy, Chung-Ang University, Seoul, Korea.
(6)Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science,
Tokyo, Japan.
(7)Pulmonary Research Group, Department of Medicine, University of Alberta,
Edmonton, Alberta, Canada.
(8)College of Pharmacy, Yeungnam University, Gyeongsan, Korea. Electronic
address: [email protected].
BACKGROUND: Extracellular signal-regulated kinases 1/2 (ERK1/2) make important
contributions to allergic responses via their regulation of degranulation,
eicosanoid production, and cytokine expression by mast cells, yet the mechanisms
underlying their positive effects on FcεRI-dependent signaling are not fully
understood. Recently, we reported that mast cell activation and anaphylaxis are
negatively regulated by AMP-activated protein kinase (AMPK). However, little is
known about the relationship between ERK1/2-mediated positive and the
AMPK-mediated negative regulation of FcεRI signaling in mast cells.
OBJECTIVE: We investigated possible interactions between ERK1/2 and AMPK in the
modulation of mast cell signaling and anaphylaxis.
METHODS: Wild-type or AMPKα2(-/-) mice, or bone marrow-derived mast cells
obtained from these mice, were treated with either chemical agents or small
interfering RNAs that modulated the activity or expression of ERK1/2 or AMPK to
evaluate the functional interplay between ERK1/2 and AMPK in FcεRI-dependent
signaling.
RESULTS: The ERK1/2 pathway inhibitor U0126 and the AMPK activator
5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside similarly inhibited
FcεRI-mediated mast cell signals in vitro and anaphylaxis in vivo.
ERK1/2-specific small interfering RNA also mimicked this effect on FcεRI
signals. Moreover, AMPKα2 knockdown or deficiency led to increased
FcεRI-mediated mast cell activation and anaphylaxis that were insensitive to
U0126 or activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside,
suggesting that the suppression of FcεRI signals by the inhibition of the ERK1/2
pathway relies largely on AMPK activation. ERK1/2 controlled AMPK activity by
regulating its subcellular translocation.
CONCLUSIONS: ERK1/2 ablated the AMPK-dependent negative regulatory axis, thereby
activating FcεRI signals in mast cells.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jaci.2014.05.001
PMID: 24948367 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22744266 | 1. Curr Opin Allergy Clin Immunol. 2012 Aug;12(4):354-60. doi:
10.1097/ACI.0b013e328355b7cb.
Drug allergy in mast cell disease.
Brockow K(1), Bonadonna P.
Author information:
(1)Department of Dermatology and Allergology, Technische Universität Munich, and
Center for Allergy and Environment, Technische Universität und Helmholtz Center
Munich, Munich, Germany. [email protected]
PURPOSE OF REVIEW: Mastocytosis in adults is associated with a history of
anaphylaxis in 22-49%. In addition, monoclonal mast cell activation syndrome has
been described presenting with anaphylaxis, especially in patients with
hymenoptera venom anaphylaxis. Data on patients with drug hypersensitivity and
mast cell diseases are scarce.
RECENT FINDINGS: Drugs are elicitors of anaphylaxis in patients with
mastocytosis. Drug hypersensitivity is only seldom described as associated with
undetected mast cell disease in the literature. Together with a single-centred
retrospective study, this data suggests that from all patients with drug-induced
anaphylaxis, probably only a minority are associated with mast cell disease.
Most of these cases in the literature are related to general anaesthesia. Thus,
for patients with mastocytosis, general anaesthesia appears to be a procedure
associated with risk of mast cell degranulation, and special precautions should
be considered.
SUMMARY: The association between immediate drug hypersensitivity and undetected
mast cell diseases appears to be moderate, but nevertheless basal serum tryptase
determination and examination for skin signs of mast cell disorders are
recommended. An ongoing European multicenter study by the European Network for
Drug Allergy will provide more information on this topic.
DOI: 10.1097/ACI.0b013e328355b7cb
PMID: 22744266 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28835513 | 1. Oncologist. 2017 Nov;22(11):1392-1399. doi: 10.1634/theoncologist.2017-0078.
Epub 2017 Aug 23.
FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell
Lung Cancer: First-Line Therapy and Beyond.
Pai-Scherf L(1), Blumenthal GM(2), Li H(2), Subramaniam S(2), Mishra-Kalyani
PS(2), He K(2), Zhao H(2), Yu J(2), Paciga M(2), Goldberg KB(2), McKee AE(2),
Keegan P(2), Pazdur R(2).
Author information:
(1)Center for Drug Evaluation and Research, U.S. Food and Drug Administration,
Silver Spring, Maryland, USA [email protected].
(2)Center for Drug Evaluation and Research, U.S. Food and Drug Administration,
Silver Spring, Maryland, USA.
On October 24, 2016, the U.S. Food and Drug Administration (FDA) approved
pembrolizumab (Keytruda; Merck & Co., Inc., https://www.merck.com) for treatment
of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors
express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test,
as follows: (a) first-line treatment of patients with mNSCLC whose tumors have
high PD-L1 expression (tumor proportion score [TPS] ≥50%), with no epidermal
growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor
aberrations, and (b) treatment of patients with mNSCLC whose tumors express
PD-L1 (TPS ≥1%), with disease progression on or after platinum-containing
chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have
disease progression on FDA-approved therapy for these aberrations prior to
receiving pembrolizumab.Approval was based on two randomized, open-label,
active-controlled trials demonstrating statistically significant improvements in
progression-free survival (PFS) and overall survival (OS) for patients
randomized to pembrolizumab compared with chemotherapy. In KEYNOTE-024, patients
with previously untreated mNSCLC who received pembrolizumab (200 mg
intravenously [IV] every 3 weeks) had a statistically significant improvement in
OS (hazard ratio [HR] 0.60; 95% confidence interval [CI]: 0.41-0.89; p = .005),
and significant improvement in PFS (HR 0.50; 95% CI: 0.37-0.68; p < .001). In
KEYNOTE-010, patients with disease progression on or after platinum-containing
chemotherapy received pembrolizumab IV 2 mg/kg, 10 mg/kg, or docetaxel 75 mg/m2
every 3 weeks. The HR and p value for OS was 0.71 (95% CI: 0.58-0.88), p < .001
comparing pembrolizumab 2 mg/kg with chemotherapy and the HR and p value for OS
was 0.61 (95% CI: 0.49-0.75), p < .001 comparing pembrolizumab 10 mg/kg with
chemotherapy.
IMPLICATIONS FOR PRACTICE: This is the first U.S. Food and Drug Administration
approval of a checkpoint inhibitor for first-line treatment of lung cancer. This
approval expands the pembrolizumab indication in second-line treatment of lung
cancer to include all patients with programmed death-ligand 1-expressing
non-small cell lung cancer.
Published 2017. This article is a U.S. Government work and is in the public
domain in the USA.
DOI: 10.1634/theoncologist.2017-0078
PMCID: PMC5679831
PMID: 28835513 [Indexed for MEDLINE]
Conflict of interest statement: Disclosures of potential conflicts of interest
may be found at the end of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/36401022 | 1. Methods Mol Biol. 2023;2587:31-41. doi: 10.1007/978-1-0716-2772-3_2.
Viltolarsen: From Preclinical Studies to FDA Approval.
Roshmi RR(1), Yokota T(2)(3).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Canada.
(2)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Canada. [email protected].
(3)The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM
Toupin Neurological Science Research Chair, Edmonton, Canada.
[email protected].
Viltolarsen is a phosphorodiamidate morpholino antisense oligonucleotide (PMO)
designed to skip exon 53 of the DMD gene for the treatment of Duchenne muscular
dystrophy (DMD), one of the most common lethal genetic disorders characterized
by progressive degeneration of skeletal muscles and cardiomyopathy. It was
developed by Nippon Shinyaku in collaboration with the National Center of
Neurology and Psychiatry (NCNP) in Japan based on the preclinical studies
conducted in the DMD dog model at the NCNP. After showing hopeful results in
pre-clinical trials and several clinical trials across North America and Japan,
it received US Food and Drug Administration (FDA) approval for DMD in 2020.
Viltolarsen restores the reading frame of the DMD gene by skipping exon 53 and
produces a truncated but functional form of dystrophin. It can treat
approximately 8-10% of the DMD patient population. This paper aims to summarize
the development of viltolarsen from preclinical trials to clinical trials to,
finally, FDA approval, and discusses the challenges that come with fighting DMD
using antisense therapy.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2772-3_2
PMID: 36401022 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27130857 | 1. J Allergy Clin Immunol. 2016 Jun;137(6):1674-1680. doi:
10.1016/j.jaci.2016.02.015. Epub 2016 Apr 26.
Human IgE-independent systemic anaphylaxis.
Finkelman FD(1), Khodoun MV(2), Strait R(3).
Author information:
(1)Division of Allergy, Immunology and Rheumatology, Department of Internal
Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio;
Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati,
Ohio; Division of Immunobiology, Cincinnati Children's Hospital Medical Center,
Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of
Medicine, Cincinnati, Ohio. Electronic address: [email protected].
(2)Division of Allergy, Immunology and Rheumatology, Department of Internal
Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio;
Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati,
Ohio.
(3)Division of Emergency Medicine, Cincinnati Children's Hospital Medical
Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati
College of Medicine, Cincinnati, Ohio.
Anaphylaxis is a rapidly developing, life-threatening, generalized or systemic
allergic reaction that is classically elicited by antigen crosslinking of
antigen-specific IgE bound to the high-affinity IgE receptor FcεRI on mast cells
and basophils. This initiates signals that induce cellular degranulation with
release and secretion of vasoactive mediators, enzymes, and cytokines. However,
IgE-independent mechanisms of anaphylaxis have been clearly demonstrated in
experimental animals. These include IgG-dependent anaphylaxis, which involves
the triggering of mediator release by IgG/antigen complex crosslinking of FcγRs
on macrophages, basophils, and neutrophils; anaphylaxis mediated by binding of
the complement-derived peptides C3a and C5a to their receptors on mast cells,
basophils, and other myeloid cells; and direct activation of mast cells by drugs
that interact with receptors on these cells. Here we review the mechanisms
involved in these IgE-independent forms of anaphylaxis and the clinical evidence
for their human relevance. We conclude that this evidence supports the existence
of all 3 IgE-independent mechanisms as important causes of human disease,
although practical and ethical considerations preclude their demonstration to
the degree of certainty possible with animal models. Furthermore, we cite
evidence that different clinical situations can suggest different mechanisms as
having a primal role in anaphylaxis and that IgE-dependent and distinct
IgE-independent mechanisms can act together to increase anaphylaxis severity. As
specific agents become available that can interfere with mechanisms involved in
the different types of anaphylaxis, recognition of specific types of anaphylaxis
is likely to become important for optimal prophylaxis and therapy.
Published by Elsevier Inc.
DOI: 10.1016/j.jaci.2016.02.015
PMCID: PMC7607869
PMID: 27130857 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33285037 | 1. Ann Clin Transl Neurol. 2020 Dec;7(12):2393-2408. doi: 10.1002/acn3.51235.
Epub 2020 Dec 7.
Viltolarsen in Japanese Duchenne muscular dystrophy patients: A phase 1/2 study.
Komaki H(1), Takeshima Y(2), Matsumura T(3), Ozasa S(4), Funato M(5), Takeshita
E(6), Iwata Y(7), Yajima H(7), Egawa Y(8), Toramoto T(8), Tajima M(8), Takeda
S(9).
Author information:
(1)Translational Medical Center, National Center of Neurology and Psychiatry,
Kodaira, Tokyo, Japan.
(2)Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Hyogo,
Japan.
(3)Department of Neurology, National Hospital Organization Osaka Toneyama
Medical Center, Toyonaka, Osaka, Japan.
(4)Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Kumamoto,
Japan.
(5)Department of Pediatrics, National Hospital Organization Nagara Medical
Center, Gifu, Japan.
(6)Department of Child Neurology, National Center of Neurology and Psychiatry,
National Center Hospital, Kodaira, Tokyo, Japan.
(7)Department of Rehabilitation, National Center of Neurology and Psychiatry,
National Center Hospital, Kodaira, Tokyo, Japan.
(8)Global Clinical Development Department, Nippon Shinyaku Co., Ltd., Kyoto,
Kyoto, Japan.
(9)National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
OBJECTIVE: The novel morpholino antisense oligonucleotide viltolarsen targets
exon 53 of the dystrophin gene, and could be an effective treatment for patients
with Duchenne muscular dystrophy (DMD). We investigated viltolarsen's ability to
induce dystrophin expression and examined its safety in DMD patients.
METHODS: In this open-label, multicenter, parallel-group, phase 1/2, exploratory
study, 16 ambulant and nonambulant males aged 5-12 years with DMD received
viltolarsen 40 or 80 mg/kg/week via intravenous infusion for 24 weeks. Primary
endpoints were dystrophin expression and exon 53 skipping levels.
RESULTS: In western blot analysis, mean changes in dystrophin expression (%
normal) from baseline to Weeks 12 and 24 were - 1.21 (P = 0.5136) and 1.46
(P = 0.1636), respectively, in the 40 mg/kg group, and 0.76 (P = 0.2367) and
4.81 (P = 0.0536), respectively, in the 80 mg/kg group. The increase in mean
dystrophin level at Weeks 12 and 24 was significant in the 80 mg/kg group
(2.78%; P = 0.0364). Patients receiving 80 mg/kg showed a higher mean exon 53
skipping level (42.4%) than those receiving 40 mg/kg (21.8%). All adverse events
were judged to be mild or moderate in intensity and none led to study
discontinuation.
INTERPRETATION: Treatment with viltolarsen 40 or 80 mg/kg elicited an increasing
trend in dystrophin expression and exon 53 skipping levels, and was safe and
well tolerated. The decline in motor function appeared less marked in patients
with higher dystrophin levels; this may warrant further investigation. This
study supports the potential clinical benefit of viltolarsen.
© 2020 The Authors. Annals of Clinical and Translational Neurology published by
Wiley Periodicals LLC on behalf of American Neurological Association.
DOI: 10.1002/acn3.51235
PMCID: PMC7732240
PMID: 33285037 [Indexed for MEDLINE]
Conflict of interest statement: H.K. has received grants from Taiho, Pfizer
Japan, Nippon Shinyaku, Daiichi Sankyo, Chugai, PTC Therapeutics; and personal
fees from Sarepta Therapeutics. Y.T. has received grants from Nippon Shinyaku;
and personal fees from Daiichi Sankyo and Biogen. T.M. has received grants from
Nippon Shinyaku. S.O. has received grants from Nippon Shinyaku, Biogen, and PTC
Therapeutics. M.F. has received grants from Nippon Shinyaku and Taiho. E.T. has
received grants from Taiho, Nippon Shinyaku, Daiichi Sankyo, and Takeda; and
personal fees from Pfizer Japan. Y.I. has received grants from Taiho, Nippon
Shinyaku, and Daiichi Sankyo; and personal fees from Astellas Pharma. H.Y. has
received grants from Taiho, Nippon Shinyaku, and Daiichi Sankyo; and personal
fees from Biogen. S.T. is an officer and board member of the National Center of
Neurology and Psychiatry; and has received grants from Nippon Shinyaku, Daiichi
Sankyo and The Noguchi Institute. Y.E., M.T., and T.T. are employees of Nippon
Shinyaku Co., Ltd. |
http://www.ncbi.nlm.nih.gov/pubmed/35634851 | 1. J Neuromuscul Dis. 2022;9(4):493-501. doi: 10.3233/JND-220811.
Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with
Duchenne Muscular Dystrophy.
Clemens PR(1)(2), Rao VK(3), Connolly AM(4), Harper AD(5), Mah JK(6), McDonald
CM(7), Smith EC(8), Zaidman CM(9), Nakagawa T(10); CINRG DNHS Investigators;
Hoffman EP(11).
Author information:
(1)Department of Neurology, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania.
(2)Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania.
(3)Division of Neurology, Ann and Robert H. Lurie Children's Hospital of
Chicago, Chicago, Illinois.
(4)Division of Neurology, Nationwide Children's Hospital, The Ohio State
University College of Medicine, Columbus, Ohio.
(5)Children's Hospital of Richmond at Virginia Commonwealth University,
Richmond, Virginia.
(6)Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.
(7)Department of Physical Medicine and Rehabilitation, Department of Pediatrics,
UC Davis Health, University of California, Davis, Sacramento, California.
(8)Duke University Medical Center, Durham, North Carolina.
(9)Department of Neurology, Washington University at St Louis, St Louis,
Missouri.
(10)NS Pharma, Inc, Paramus, New Jersey.
(11)Department of Pharmaceutical Sciences, State University of New York at
Binghamton, Binghamton, New York.
BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused
by mutations in the DMD gene resulting in an absence of functional dystrophin
protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase
endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes
in viltolarsen treated patients were compared to a matched historical control
group.
OBJECTIVE: To evaluate long-term efficacy and safety of the anti-sense
oligonucleotide viltolarsen in the treatment of patients with DMD amenable to
exon 53 skipping therapy.
METHODS: This trial (NCT03167255) is the extension of a previously published
24-week trial in North America (NCT02740972) that examined dystrophin levels,
timed function tests compared to a matched historical control group (Cooperative
International Neuromuscular Research Group Duchenne Natural History Study, CINRG
DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53
skipping who were treated with viltolarsen. Both groups were treated with
glucocorticoids. All 16 participants elected to enroll in this long-term trial
(up to 192 weeks) to continue evaluation of motor function and safety.
RESULTS: Time to stand from supine and time to run/walk 10 meters showed
stabilization from baseline through week 109 for viltolarsen-treated
participants whereas the historical control group showed decline (statistically
significant differences for multiple timepoints). Safety was similar to that
observed in the previous 24-week trial, which was predominantly mild. There have
been no treatment-related serious adverse events and no discontinuations.
CONCLUSIONS: Based on these results at over 2 years, viltolarsen can be a new
treatment option for patients with DMD amenable to exon 53 skipping.
DOI: 10.3233/JND-220811
PMCID: PMC9398057
PMID: 35634851 [Indexed for MEDLINE]
Conflict of interest statement: a. Dr Clemens has received grants from NS Pharma
during the conduct of the study as well as grants from Spark Therapeutics,
Amicus Therapeutics, Sanofi Genzyme, ReveraGen BioPharma, NIH, MDA, and TRiNDS
and personal fees from Epirium, outside the submitted work. b. Dr Rao has
received grants and personal fees from NS Pharma during the conduct of the study
and nonfinancial support from Ann and Robert H. Lurie Children’s Hospital of
Chicago during the conduct of the study as well as personal fees from Biogen,
Avexis/Novartis, Capricor, Regenxbio, Genentech-Roche, Scholar Rock, PTC
Therapeutics, Sarepta Therapeutics, France Foundation, and MDA outside the
submitted work. c. Dr Connolly has received grants from the Washington
University School of Medicine and TRiNDS during the conduct of the study as well
as grants from Sarepta Therapeutics, AveXis, and Fibrogen and personal fees from
Sarepta Therapeutics, Scholar Rock, Genentech-Roche, Dyne Therapeutics, and
Edgewise Therapeutics outside the submitted work. d. Dr Harper has received
grants from NS Pharma, Italfarmaco, ReveraGen BioPharma, Catabasis
Pharmaceuticals, Astellas Pharmaceuticals, MLBio, AveXis, CSL Behring, Teva
Pharmaceutical Industries, Novartis, National Institutes of Health, and US
Centers for Disease Control and Prevention. e. Dr Mah has received grants from
NS Pharma during the conduct of the study as well as personal fees from PTC
Therapeutics, Biogen and Roche and grants from PTC Therapeutics, Pfizer, Roche,
Sarepta Therapeutics, Italfarmaco, Novartis, Biogen, ReveraGen BioPharma,
Catabasis Pharmaceuticals, Sanofi-Genzyme, and Alberta Children’s Hospital
Foundation outside the submitted work. f. Dr McDonald has received grants from
NS Pharma during the conduct of the study as well as personal fees from Avidity
Biosciences, Astellas, Capricor Therapeutics, Catabasis Pharmaceuticals,
Edgewise Therapeutics, Entrada Therapeutics, Epirium Bio, FibroGen, Italfarmaco,
Pfizer, PTC Therapeutics, Roche, Santhera Pharmaceuticals, Solid Biosciences,
and Sarepta Therapeutics outside the submitted work. g. Dr Smith has received
personal fees from NS Pharma during the conduct of the study as well as personal
fees from Pfizer and Sarepta Therapeutics outside the submitted work. h. Dr
Zaidman has received grant support from Biogen and Novartis outside the
submitted work. i. Mr Nakagawa is an employee of NS Pharma, Inc. j. Dr Hoffman
has received fees from NS Pharma, holds stock and held oversight roles in AGADA
Biosciences and TRiNDS during the conduct of the study, and holds stock and has
management roles in ReveraGen BioPharma outside the submitted work. |
http://www.ncbi.nlm.nih.gov/pubmed/32317620 | 1. Am J Case Rep. 2020 Apr 22;21:e922715. doi: 10.12659/AJCR.922715.
A Case of Nutcracker Syndrome Combined with Wilkie Syndrome with Unusual
Clinical Presentation.
Farina R(1), Iannace FA(1), Foti PV(1), Conti A(1), Inì C(1), Libra F(1),
Fanzone L(1), Coronella ME(1), Santonocito S(1), Basile A(1).
Author information:
(1)Radiodiagnostic and Radiotherapy Unit, Department of Medical and Surgical
Sciences and Advanced Technologies "GF Ingrassia", University of Catania,
Catania, Italy.
BACKGROUND Nutcracker syndrome and Wilkie's syndrome are rare vascular diseases
due to the abnormal course of the superior mesenteric artery originating from
the abdominal aorta with reduced angle (<22°) and consequent compression of the
left renal vein (nutcracker) and duodenum (Wilkie). Here, we report the case of
a patient with a rare combination of these 2 syndromes and with unusual clinical
manifestation of post-prandial pain. CASE REPORT We describe the case of a young
male patient with rapid weight loss, coupled with post-prandial abdominal pain,
with sub-acute onset, not associated with other symptoms. The ultrasound
examination found an aorto-mesenteric angle of 18° and compression of the left
renal vein and left varicocele. A CT study was performed to exclude oncological
diseases and/or other pathologies responsible for the pain and weight loss,
which confirmed the ultrasound findings and showed compression of the third part
of the duodenum. The patient underwent endovascular treatment, with stent
placement in the left renal vein, which resolved the vascular compression and of
the duodenum, with regression of symptoms. CONCLUSIONS The ultrasound scan
promptly highlighted the reduction of the aorto-mesenteric angle and the signs
of venous congestion of the left renal vein. Based on this experience, in
patients with weight loss and post-prandial pain, in our opinion, diagnostic
investigations should also be extended to the study of the aorto-mesenteric
angle to confirm or exclude any vascular and/or duodenal compression.
DOI: 10.12659/AJCR.922715
PMCID: PMC7193224
PMID: 32317620 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: None declared Conflict of
interest None. |
http://www.ncbi.nlm.nih.gov/pubmed/32116320 | 1. Cir Cir. 2020;88(2):185-188. doi: 10.24875/CIRU.19001195.
Wilkie's syndrome as a cause of bowel obstruction in adults: A case report.
[Article in English]
Requena-López AA(1), Mata-Samperio BK(1), Cuadra-Reyes LA(1), Casillas-Vargas
R(1).
Author information:
(1)Departamento de Cirugía General, Centro Médico, Instituto de Seguridad Social
del Estado de México (ISSEMyM), Ecatepec, Estado de México, México.
BACKGROUND: The superior mesenteric artery (SMA) syndrome, also known as
Wilkie's syndrome, is one of the rarest causes of small bowel obstruction.
CLINICAL CASE: A 36-year-old female patient, with a medical history of diabetes
mellitus type 2, arrived at the emergency department with upper intestinal
obstruction; a study protocol is made, integrating the diagnosis of Wilkie's
syndrome. We performed a laparoscopic duodenojejunostomy, the patient did well
in the post-operative period.
CONCLUSIONS: Laparoscopic duodenojejunostomy is a practical option to treat
Wilkie's syndrome. It provides definitive treatment with the advantages and
benefits of minimally invasive surgery.
Publisher: ANTECEDENTES: El síndrome de la arteria mesentérica superior o
síndrome de Wilkie es una de las causas más raras de obstrucción del intestino
Delgado.
CASO CLÍNICO: Mujer de 36 años, con antecedente de diabetes mellitus tipo 2, que
llegó al servicio de urgencias con un cuadro de oclusión intestinal alta. Se
realizó protocolo de estudio, integrando el diagnóstico de síndrome de Wilkie.
Se realizó anastomosis duodenoyeyunal laparoscópica y la paciente cursó con
adecuada evolución posquirúrgica.
CONCLUSIONES: La anastomosis duodenoyeyunal laparoscópica es una opción práctica
en el tratamiento del síndrome de Wilkie, con las ventajas y beneficios de la
cirugía de mínima invasión.
Copyright: © 2020 Permanyer.
DOI: 10.24875/CIRU.19001195
PMID: 32116320 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33655184 | 1. Spartan Med Res J. 2020 Oct 30;5(2):13485. doi: 10.51894/001c.13485.
Wilkie's Weight Loss Wonder, A Case Series.
Haidar A(1), Davies A(1), Hussain A(1), Gregerson S(2), Thammineni D(1), Markus
J(1).
Author information:
(1)McLaren Macomb.
(2)Michigan State University.
INTRODUCTION: Wilkie's Syndrome, also known as Superior Mesenteric Artery
Syndrome (SMAS), is a rare cause of bowel obstruction that can contribute to
vague abdominal symptoms on clinical presentation. This syndrome occurs when the
aortomesenteric angle decreases, compressing the third portion of the duodenum
between the aorta and the superior mesenteric artery. An acute decrease in the
mesenteric fat pad cushion between these two blood vessels is the primary
etiology, although other causes (e.g., anatomical, postoperative, functional,
and pubescent etiologies) have also been described.
CASE PRESENTATION: In the present cases, 2 females with a common history of
recent weight loss presented to our institution with similar symptoms of
abdominal pain, nausea and vomiting. Each patient was subsequently diagnosed
with SMAS following imaging studies. Both patients experienced successful
resolution of symptoms with conservative nutritional management.
DISCUSSION: Common presenting complaints of SMAS include nausea, vomiting, early
satiety and postprandial pain. These symptoms overlap with other
gastrointestinal disorders (i.e., mesenteric ischemia, intestinal volvulus,
peptic ulcer disease) making diagnosis difficult. SMAS can be identified through
imaging modalities including barium studies and computer tomography. First line
therapies typically include conservative nutritional support and promotion of
weight gain. If conservative therapies fail, various surgical procedures can be
pursued. Delayed diagnosis can lead to further pathological sequelae, including
duodenal compromise, ischemia and necrosis. As the syndrome progresses, success
of conservative nutritional support is less likely, and surgical correction
becomes increasingly necessary.
CONCLUSION: Therefore, a clinical goal for SMAS should include as swift a
recognition and diagnosis as possible.
DOI: 10.51894/001c.13485
PMCID: PMC7746062
PMID: 33655184 |
http://www.ncbi.nlm.nih.gov/pubmed/33083170 | 1. Cureus. 2020 Sep 15;12(9):e10467. doi: 10.7759/cureus.10467.
Wilkie's Syndrome as a Rare Cause of Duodenal Obstruction: Perspicacity Is in
the Radiological Details.
Al Faqeeh AA(1), Syed MK(1), Ammar M(1), Almas T(2), Syed S(2).
Author information:
(1)Pediatric Surgery, King Fahad Hospital, Al Baha, SAU.
(2)Internal Medicine, Royal College of Surgeons in Ireland, Dublin, IRL.
Superior mesenteric artery syndrome, or Wilkie's syndrome, is an unexpected
cause of upper gastrointestinal tract obstruction. The exact incidence of the
condition remains unknown, and limited case reports are present in the
literature. The obstruction results in the compression of the third part of the
duodenum between the superior mesenteric artery and aorta. It is widely known
that a lack of subcutaneous tissue in the area can precipitate the obstruction
by significantly reducing the aortomesenteric angle. Wilkie's syndrome presents
a clinically diagnostic challenge as patients initially remain undiagnosed with
relapsing episodes of upper abdominal pain and bilious vomiting. In some cases,
an acute obstruction may arise. Undertaking an initial contrast study of the
upper gastrointestinal tract and a CT scan are required to confirm the diagnosis
of the condition. In the present study, we elucidate the case of a 12-year-old
girl who presented with upper abdominal pain and bouts of bilious vomiting. Upon
extensive diagnostic evaluation, Wilkie's syndrome was diagnosed. Since the
patient failed to respond to conservative treatment, a laparotomy with
subsequent duodenojejunostomy was undertaken. The postoperative recovery of the
patient was uneventful with no recurrence of symptoms on follow-up.
Copyright © 2020, Al Faqeeh et al.
DOI: 10.7759/cureus.10467
PMCID: PMC7566986
PMID: 33083170
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/32821627 | 1. Cureus. 2020 Aug 13;12(8):e9715. doi: 10.7759/cureus.9715.
Predictors of Superior Mesenteric Artery Syndrome: Evidence from a Case-Control
Study.
Alzerwi NAN(1).
Author information:
(1)Surgery, Majmaah University, Ministry of Education, Al-Majmaah, SAU.
Introduction Superior mesenteric artery (SMA) or Wilkie's syndrome is a rare
condition arising due to compression of the third part of the duodenum between
the abdominal aorta and the superior mesenteric artery. It is important to
explore factors which help in suspicion and early diagnosis of the condition.
The aim of this study was to find out if measurements of aortomesenteric angle
and distance can predict the occurrence of SMA syndrome. Another objective was
to find out if the BMI was correlated with the aortomesenteric angle and
distance of the patients. Methods A retrospective hospital-based case-control
study was conducted in Qimat Rai Gupta Central hospital, Haryana, India from
2018-2020. Out of total 2100 records of acute and chronic abdominal pain
patients, only seven cases of Wilkie's syndrome were confirmed via
Contrast-Enhanced Computed Tomography (CECT). Information on age, gender, BMI,
duration of symptoms, clinical presentation, aortomesenteric angle, and distance
was compared among three groups: Group I-SMA syndrome patients (N=7), Group II-
acute abdominal pain patients (N=14) and Group III- chronic abdominal pain
patients (N=14). Results The hospital prevalence of Wilkie's was found to be
0.3%. The median age of patients in Group I corresponded to 26 years as opposed
to Group II (31.5years) and Group III (30.5 years). There was a statistically
significant reduction in the aortomesenteric angle and distance of Group I
patients (22º, 6mm) as compared to both Group II (52.5º, 11mm) and Group III
patients (52º, 11mm). A moderate correlation of BMI was found with
aortomesenteric angle (r=0.479) and distance (r=0.357). Conclusions There was a
significant reduction in the aortomesenteric angle and distance of the SMA
patients as compared to both patients having acute and chronic abdominal pain.
The BMI of patients was positively correlated to aortomesenteric angle and
distance to the moderate level. Thus BMI along with aortomesenteric angle and
distance can predict the presence of SMA syndrome.
Copyright © 2020, Alzerwi et al.
DOI: 10.7759/cureus.9715
PMCID: PMC7429617
PMID: 32821627
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/32399444 | 1. Eur J Case Rep Intern Med. 2020 Mar 23;7(5):001557. doi: 10.12890/2020_001557.
eCollection 2020.
Epigastric Pain and Weight Loss - A Case of Wilkie's Syndrome.
Lima Silva A(1), Antunes D(1), Cordeiro E Cunha J(1), Nogueira R(1), Fernandes
D(1), Salazar T(1), Madureira Pinto C(1).
Author information:
(1)Internal Medicine Department, Centro Hospitalar do Médio Ave, Unidade de
Famalicão, Vila Nova de Famalicão, Portugal.
Superior mesenteric artery syndrome (SMA syndrome) or Wilkie's syndrome is a
rare etiology of duodenal obstruction due to compression of the third portion of
the duodenum between the superior mesenteric artery and the aorta. Physical and
laboratory findings are often non-specific but imaging methods are useful for
diagnosing the condition. A 46-year-old female patient presented to the
outpatient clinic of our internal medicine department with a 2-year history of
epigastric pain, nausea, early satiety and weight loss of 15 kg. Previous
studies were inconclusive. The patient underwent computed tomography
enterography and its findings were consistent with SMA syndrome. Currently the
patient is being followed by General Surgery and Nutrition and is under
nutritional measures in order to optimize her body mass index to decrease
possible surgical complications. This case report emphasizes the importance of
clinical suspicion and careful investigation when considering less common
etiologies for frequent gastrointestinal symptoms.
LEARNING POINTS: Superior mesenteric artery syndrome is a rare cause of upper
gastrointestinal system obstruction and its diagnosis is often delayed.This
syndrome should be suspected in the differential diagnosis of patients with
persistent nausea, abdominal pain and significant weight loss.
© EFIM 2020.
DOI: 10.12890/2020_001557
PMCID: PMC7213823
PMID: 32399444
Conflict of interest statement: Conflicts of Interests: The Authors declare that
there are no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35680848 | 1. Signal Transduct Target Ther. 2022 Jun 9;7(1):181. doi:
10.1038/s41392-022-00999-9.
PROTACs: great opportunities for academia and industry (an update from 2020 to
2021).
He M(#)(1), Cao C(#)(1)(2), Ni Z(#)(1), Liu Y(1), Song P(1), Hao S(1), He Y(1),
Sun X(1), Rao Y(3)(4).
Author information:
(1)Ministry of Education (MOE) Key Laboratory of Protein Sciences, School of
Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry &
Chemical Biology, Tsinghua University, 100084, Beijing, P. R. China.
(2)Tsinghua-Peking Center for Life Sciences, 100084, Beijing, P. R. China.
(3)Ministry of Education (MOE) Key Laboratory of Protein Sciences, School of
Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry &
Chemical Biology, Tsinghua University, 100084, Beijing, P. R. China.
[email protected].
(4)School of Pharmaceutical Sciences, Zhengzhou University, 450001, Zhengzhou,
China. [email protected].
(#)Contributed equally
PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation
strategy that has emerged in recent years. It uses bifunctional small molecules
to induce the ubiquitination and degradation of target proteins through the
ubiquitin-proteasome system. PROTACs can not only be used as potential clinical
treatments for diseases such as cancer, immune disorders, viral infections, and
neurodegenerative diseases, but also provide unique chemical knockdown tools for
biological research in a catalytic, reversible, and rapid manner. In 2019, our
group published a review article "PROTACs: great opportunities for academia and
industry" in the journal, summarizing the representative compounds of PROTACs
reported before the end of 2019. In the past 2 years, the entire field of
protein degradation has experienced rapid development, including not only a
large increase in the number of research papers on protein-degradation
technology but also a rapid increase in the number of small-molecule degraders
that have entered the clinical and will enter the clinical stage. In addition to
PROTAC and molecular glue technology, other new degradation technologies are
also developing rapidly. In this article, we mainly summarize and review the
representative PROTACs of related targets published in 2020-2021 to present to
researchers the exciting developments in the field of protein degradation. The
problems that need to be solved in this field will also be briefly introduced.
© 2022. The Author(s).
DOI: 10.1038/s41392-022-00999-9
PMCID: PMC9178337
PMID: 35680848 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35412837 | 1. J Med Chem. 2022 Apr 28;65(8):6116-6132. doi: 10.1021/acs.jmedchem.1c02155.
Epub 2022 Apr 12.
In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses.
Liao J(1), Nie X(1), Unarta IC(2), Ericksen SS(3), Tang W(1)(2)(3).
Author information:
(1)School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin
53705, United States.
(2)Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin
53706, United States.
(3)Drug Development Core, UW Carbone Cancer Center, School of Medicine and
Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705, United
States.
Proteolysis targeting chimeras (PROTACs) are molecules that induce protein
degradation via formation of ternary complexes between an E3 ubiquitin ligase
and a target protein. The rational design of PROTACs requires accurate knowledge
of the native configuration of the PROTAC-induced ternary complex. This study
demonstrates that native and non-native ternary complex poses can be
distinguished based on the pose occupancy time in MD, where native poses exhibit
longer occupancy times at both room and higher temperatures. Candidate poses are
generated by MD sampling and pre-ranked by classic MM/GBSA. A specific heating
scheme is then applied to accelerate ternary pose departure, with the pose
occupancy time and fraction being measured. This scoring identifies the native
pose in all systems tested. Its success is partially attributed to the dynamic
nature of pose departure analyses, which accounts for entropic effects typically
neglected in the faster static scoring methods, while entropy plays a greater
role in protein-protein than in protein-ligand systems.
DOI: 10.1021/acs.jmedchem.1c02155
PMID: 35412837 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35671157 | 1. Chem Soc Rev. 2022 Jun 20;51(12):5214-5236. doi: 10.1039/d2cs00193d.
PROTACs: past, present and future.
Li K(1), Crews CM(1)(2)(3).
Author information:
(1)Department of Molecular, Cellular and Developmental Biology, Yale University,
New Haven, Connecticut 06511, USA. [email protected].
(2)Department of Chemistry, Yale University, New Haven, Connecticut 06511, USA.
(3)Department of Pharmacology, Yale University, New Haven, Connecticut 06511,
USA.
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules
consisting of one ligand that binds to a protein of interest (POI) and another
that can recruit an E3 ubiquitin ligase. The chemically-induced proximity
between the POI and E3 ligase results in ubiquitination and subsequent
degradation of the POI by the ubiquitin-proteasome system (UPS). The
event-driven mechanism of action (MOA) of PROTACs offers several advantages
compared to traditional occupancy-driven small molecule inhibitors, such as a
catalytic nature, reduced dosing and dosing frequency, a more potent and
longer-lasting effect, an added layer of selectivity to reduce potential
toxicity, efficacy in the face of drug-resistance mechanisms, targeting
nonenzymatic functions, and expanded target space. Here, we highlight important
milestones and briefly discuss lessons learned about targeted protein
degradation (TPD) in recent years and conjecture on the efforts still needed to
expand the toolbox for PROTAC discovery to ultimately provide promising
therapeutics.
DOI: 10.1039/d2cs00193d
PMCID: PMC10237031
PMID: 35671157 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of Interest C. M. C. is a shareholder
and consultant to Halda Therapeutics and Siduma Therapeutics. He is also a
shareholder in Arvinas Inc. |
http://www.ncbi.nlm.nih.gov/pubmed/32404196 | 1. J Hematol Oncol. 2020 May 13;13(1):50. doi: 10.1186/s13045-020-00885-3.
Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and
cancer therapy.
Li X(1), Song Y(2)(3).
Author information:
(1)Department of Pharmacology and Chemical Biology, Baylor College of Medicine,
1 Baylor Plaza, Houston, TX, 77030, USA.
(2)Department of Pharmacology and Chemical Biology, Baylor College of Medicine,
1 Baylor Plaza, Houston, TX, 77030, USA. [email protected].
(3)Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1
Baylor Plaza, Houston, TX, 77030, USA. [email protected].
Proteolysis-targeting chimera (PROTAC) has been developed to be a useful
technology for targeted protein degradation. A bifunctional PROTAC molecule
consists of a ligand (mostly small-molecule inhibitor) of the protein of
interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3).
Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which
is subjected to proteasome-mediated degradation. PROTAC complements nucleic
acid-based gene knockdown/out technologies for targeted protein reduction and
could mimic pharmacological protein inhibition. To date, PROTACs targeting ~ 50
proteins, many of which are clinically validated drug targets, have been
successfully developed with several in clinical trials for cancer therapy. This
article reviews PROTAC-mediated degradation of critical oncoproteins in cancer,
particularly those in hematological malignancies. Chemical structures, cellular
and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs
are summarized. In addition, potential advantages, challenges, and perspectives
of PROTAC technology in cancer therapy are discussed.
DOI: 10.1186/s13045-020-00885-3
PMCID: PMC7218526
PMID: 32404196 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/31004963 | 1. Curr Opin Chem Biol. 2019 Jun;50:111-119. doi: 10.1016/j.cbpa.2019.02.022.
Epub 2019 Apr 17.
Targeted protein degradation: elements of PROTAC design.
Paiva SL(1), Crews CM(2).
Author information:
(1)Molecular, Cellular, and Developmental Biology Department, Yale University,
219 Prospect Street, KBT 400, New Haven, CT, 06511, United States.
(2)Molecular, Cellular, and Developmental Biology Department, Yale University,
219 Prospect Street, KBT 400, New Haven, CT, 06511, United States. Electronic
address: [email protected].
Targeted protein degradation using Proteolysis Targeting Chimeras (PROTACs) has
emerged as a novel therapeutic modality in drug discovery. PROTACs mediate the
degradation of select proteins of interest (POIs) by hijacking the activity of
E3 ubiquitin ligases for POI ubiquitination and subsequent degradation by the
26S proteasome. This hijacking mechanism has been used to degrade various types
of disease-relevant POIs. In this review, we aim to highlight the recent
advances in targeted protein degradation and describe the challenges that need
to be addressed in order to efficiently develop potent PROTACs.
Copyright © 2019 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.cbpa.2019.02.022
PMCID: PMC6930012
PMID: 31004963 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32082969 | 1. Acta Pharm Sin B. 2020 Feb;10(2):207-238. doi: 10.1016/j.apsb.2019.08.001.
Epub 2019 Aug 13.
Degradation of proteins by PROTACs and other strategies.
Wang Y(1), Jiang X(2), Feng F(3)(2), Liu W(1), Sun H(4).
Author information:
(1)Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control
and Pharmacovigilance, Ministry of Education, China Pharmaceutical University,
Nanjing 210009, China.
(2)Department of Natural Medicinal Chemistry, China Pharmaceutical University,
Nanjing 211198, China.
(3)Jiangsu Food and Pharmaceutical Science College, Huaian 223003, China.
(4)Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing
211198, China.
Blocking the biological functions of scaffold proteins and aggregated proteins
is a challenging goal. PROTAC proteolysis-targeting chimaera (PROTAC) technology
may be the solution, considering its ability to selectively degrade target
proteins. Recent progress in the PROTAC strategy include identification of the
structure of the first ternary eutectic complex, extra-terminal
domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), and PROTAC ARV-110 has
entered clinical trials for the treatment of prostate cancer in 2019. These
discoveries strongly proved the value of the PROTAC strategy. In this
perspective, we summarized recent meaningful research of PROTAC, including the
types of degradation proteins, preliminary biological data in vitro and in vivo,
and new E3 ubiquitin ligases. Importantly, the molecular design, optimization
strategy and clinical application of candidate molecules are highlighted in
detail. Future perspectives for development of advanced PROTAC in medical fields
have also been discussed systematically.
© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica,
Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
DOI: 10.1016/j.apsb.2019.08.001
PMCID: PMC7016280
PMID: 32082969 |
http://www.ncbi.nlm.nih.gov/pubmed/33160761 | 1. Eur J Med Chem. 2021 Jan 15;210:112981. doi: 10.1016/j.ejmech.2020.112981.
Epub 2020 Oct 31.
Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent
progress and future challenges.
Zeng S(1), Huang W(1), Zheng X(2), Liyan Cheng(2), Zhang Z(3), Wang J(4), Shen
Z(5).
Author information:
(1)Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province,
Institute of Materia Medica, Hangzhou Medical College, Hangzhou, 310013, PR
China; School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, PR China.
(2)Center for Molecular Medicine, Hangzhou Medical College, Hangzhou, 310013, PR
China.
(3)Department of Drug Platform of Small Molecules, HangZhou ZhongMei HuaDong
Pharmaceutical CO, LTD, 866 Moganshan Road, Hangzhou, 310011, PR China.
(4)School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, PR China.
(5)Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province,
Institute of Materia Medica, Hangzhou Medical College, Hangzhou, 310013, PR
China; School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, PR China.
Electronic address: [email protected].
Proteolysis targeting chimera (PROTAC), hijacking protein of interest (POI) and
recruiting E3 ligase for target degradation via the ubiquitin-proteasome
pathway, is a novel drug discovery paradigm which has been widely used as
biological tools and medicinal molecules with the potential of clinical
application value. Currently, ARV-110, an orally small molecule PROTAC was
designed to specifically target Androgen receptor (AR), firstly enters clinical
phase I trials for the treatment of metastatic castration-resistant prostate
cancer, which turns a new avenue for the development of PROTAC. We herein
provide a detail summary on the latest one year progress of PROTAC target
various proteins and elucidate the advantages of PROTAC technology. Finally, the
potential challenges of this vibrant field are also discussed.
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.ejmech.2020.112981
PMID: 33160761 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper. |
http://www.ncbi.nlm.nih.gov/pubmed/33010159 | 1. Nucleic Acids Res. 2021 Jan 8;49(D1):D1381-D1387. doi: 10.1093/nar/gkaa807.
PROTAC-DB: an online database of PROTACs.
Weng G(1)(2), Shen C(1), Cao D(3), Gao J(1), Dong X(1), He Q(1), Yang B(1), Li
D(1), Wu J(4), Hou T(1)(2).
Author information:
(1)Innovation Institute for Artificial Intelligence in Medicine of Zhejiang
University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou
310058, Zhejiang, China.
(2)State Key Lab of CAD&CG, Zhejiang University, Hangzhou 310058, Zhejiang,
China.
(3)Xiangya School of Pharmaceutical Sciences, Central South University, Changsha
410004, Hunan, China.
(4)College of Computer Science and Technology, Zhejiang University, Hangzhou
310058, Zhejiang, China.
Proteolysis-targeting chimeras (PROTACs), which selectively degrade targeted
proteins by the ubiquitin-proteasome system, have emerged as a novel therapeutic
technology with potential advantages over traditional inhibition strategies. In
the past few years, this technology has achieved substantial progress and two
PROTACs have been advanced into phase I clinical trials. However, this
technology is still maturing and the design of PROTACs remains a great
challenge. In order to promote the rational design of PROTACs, we present
PROTAC-DB, a web-based open-access database that integrates structural
information and experimental data of PROTACs. Currently, PROTAC-DB consists of
1662 PROTACs, 202 warheads (small molecules that target the proteins of
interest), 65 E3 ligands (small molecules capable of recruiting E3 ligases) and
806 linkers, as well as their chemical structures, biological activities, and
physicochemical properties. Except the biological activities of warheads and E3
ligands, PROTAC-DB also provides the degradation capacities, binding affinities
and cellular activities for PROTACs. PROTAC-DB can be queried with two general
searching approaches: text-based (target name, compound name or ID) and
structure-based. In addition, for the convenience of users, a filtering tool for
the searching results based on the physicochemical properties of compounds is
also offered. PROTAC-DB is freely accessible at
http://cadd.zju.edu.cn/protacdb/.
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkaa807
PMCID: PMC7778940
PMID: 33010159 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28379698 | 1. J Med Chem. 2018 Jan 25;61(2):482-491. doi: 10.1021/acs.jmedchem.6b01872. Epub
2017 Apr 17.
Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting
Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals).
Schiedel M(1), Herp D(1), Hammelmann S(1), Swyter S(1), Lehotzky A(2), Robaa
D(3), Oláh J(2), Ovádi J(2), Sippl W(3), Jung M(1)(4).
Author information:
(1)Institute of Pharmaceutical Sciences, University of Freiburg , Albertstraße
25, 79104 Freiburg im Breisgau, Germany.
(2)Institute of Enzymology, Research Centre for Natural Sciences, Hungarian
Academy of Sciences , Magyar Tudósok körútja 2, H 1117 Budapest, Hungary.
(3)Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg ,
Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
(4)Freiburg Institute of Advanced Studies (FRIAS), University of Freiburg ,
Albertstraße 19, 79104 Freiburg im Breisgau, Germany.
Here we report the development of a proteolysis targeting chimera (PROTAC) based
on the combination of the unique features of the sirtuin rearranging ligands
(SirReals) as highly potent and isotype-selective Sirt2 inhibitors with
thalidomide, a bona fide cereblon ligand. For the first time, we report the
formation of a PROTAC by Cu(I)-catalyzed cycloaddition of a thalidomide-derived
azide to an alkynylated inhibitor. This thalidomide-derived azide as well as the
highly versatile linking strategy can be readily adapted to alkynylated ligands
of other targets. In HeLa cells, our SirReal-based PROTAC induced
isotype-selective Sirt2 degradation that results in the hyperacetylation of the
microtubule network coupled with enhanced process elongation. Thus, our
SirReal-based PROTAC is the first example of a probe that is able to chemically
induce the degradation of an epigenetic eraser protein.
DOI: 10.1021/acs.jmedchem.6b01872
PMID: 28379698 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36300631 | 1. Nucleic Acids Res. 2023 Jan 6;51(D1):D1367-D1372. doi: 10.1093/nar/gkac946.
PROTAC-DB 2.0: an updated database of PROTACs.
Weng G(1)(2), Cai X(1)(3), Cao D(4), Du H(1), Shen C(1), Deng Y(2), He Q(1)(3),
Yang B(1), Li D(1), Hou T(1).
Author information:
(1)Innovation Institute for Artificial Intelligence in Medicine of Zhejiang
University, College of Pharmaceutical Sciences, Zhejiang University,
Hangzhou 310058, Zhejiang, China.
(2)CarbonSilicon AI Technology Co., Ltd, Hangzhou 310018, Zhejiang, China.
(3)Center for Drug Safety Evaluation and Research, Zhejiang Province Key
Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou 310058, Zhejiang, China.
(4)Xiangya School of Pharmaceutical Sciences, Central South University,
Changsha 410004, Hunan, China.
Proteolysis targeting chimeras (PROTACs), which harness the ubiquitin-proteasome
system to selectively induce targeted protein degradation, represent an emerging
therapeutic technology with the potential to modulate traditional undruggable
targets. Over the past few years, this technology has moved from academia to
industry and more than 10 PROTACs have been advanced into clinical trials.
However, designing potent PROTACs with desirable drug-like properties still
remains a great challenge. Here, we report an updated online database, PROTAC-DB
2.0, which is a repository of structural and experimental data about PROTACs. In
this 2nd release, we expanded the number of PROTACs to 3270, which corresponds
to a 96% expansion over the first version. Meanwhile, the numbers of warheads
(small molecules targeting the proteins of interest), linkers, and E3 ligands
(small molecules recruiting E3 ligases) have increased to over 360, 1500 and 80,
respectively. In addition, given the importance and the limited number of the
crystal target-PROTAC-E3 ternary complex structures, we provide the predicted
ternary complex structures for PROTACs with good degradation capability using
our PROTAC-Model method. To further facilitate the analysis of PROTAC data, a
new filtering strategy based on the E3 ligases is also added. PROTAC-DB 2.0 is
available online at http://cadd.zju.edu.cn/protacdb/.
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkac946
PMCID: PMC9825472
PMID: 36300631 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35242765 | 1. Front Cell Dev Biol. 2022 Feb 15;10:854352. doi: 10.3389/fcell.2022.854352.
eCollection 2022.
Proteolysis-Targeting Chimera (PROTAC): Is the Technology Looking at the
Treatment of Brain Tumors?
Lospinoso Severini L(1), Bufalieri F(1), Infante P(1), Di Marcotullio L(1)(2).
Author information:
(1)Department of Molecular Medicine, University of Rome La Sapienza, Rome,
Italy.
(2)Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza,
Rome, Italy.
Post-translational modifications, such as ubiquitylation, need to be tightly
controlled to guarantee the accurate localization and activity of proteins.
Ubiquitylation is a dynamic process primarily responsible for
proteasome-mediated degradation of substrate proteins and crucial for both
normal homeostasis and disease. Alterations in ubiquitylation lead to the
upregulation of oncoproteins and/or downregulation of tumor suppressors, thus
concurring in tumorigenesis. PROteolysis-TArgeting Chimera (PROTAC) is an
innovative strategy that takes advantage by the cell's own Ubiquitin-Proteasome
System (UPS). Each PROTAC molecule is composed by a ligand that recruits the
target protein of interest (POI), a ligand specific for an E3 ubiquitin ligase
enzyme, and a linker that connects these units. Upon binding to the POI, the
PROTAC recruits the E3 inducing ubiquitylation-dependent proteasome degradation
of the POI. To date, PROTAC technology has entered in clinical trials for
several human cancers. Here, we will discuss the advantages and limitations of
PROTACs development and safety considerations for their clinical application.
Furthermore, we will review the potential of PROTAC strategy as therapeutic
option in brain tumor, focusing on glioblastoma.
Copyright © 2022 Lospinoso Severini, Bufalieri, Infante and Di Marcotullio.
DOI: 10.3389/fcell.2022.854352
PMCID: PMC8886235
PMID: 35242765
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35311871 | 1. Chem Commun (Camb). 2022 Apr 7;58(29):4635-4638. doi: 10.1039/d2cc00272h.
Selective degradation of histone deacetylase 8 mediated by a proteolysis
targeting chimera (PROTAC).
Chotitumnavee J(1)(2), Yamashita Y(1), Takahashi Y(2), Takada Y(1), Iida
T(1)(2), Oba M(2), Itoh Y(1)(2), Suzuki T(1)(2).
Author information:
(1)SANKEN, Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan.
[email protected].
(2)Graduate School of Medical Science, Kyoto Prefectural University of Medicine,
1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-0823, Japan.
We developed a first-in-class proteolysis targeting chimera (PROTAC) for
selective degradation of histone deacetylase 8 (HDAC8). The PROTAC induced
degradation of HDAC8 without affecting the levels of other HDACs in cellular
assays, and inhibited the growth of T-cell leukemia Jurkat cells more potently
than a conventional HDAC8 inhibitor.
DOI: 10.1039/d2cc00272h
PMID: 35311871 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36321238 | 1. Curr Drug Discov Technol. 2023;20(2):e311022210504. doi:
10.2174/1570163820666221031124612.
PROTAC: A Novel Drug Delivery Technology for Targeting Proteins in Cancer Cells.
Bala R(1), Sindhu RK(2), Madaan R(1), Yadav SK(1).
Author information:
(1)Chitkara College of Pharmacy, Chitkara University, Punjab, India.
(2)School of Pharmacy, Sharda University, Greater Noida, Gautam Buddha Nagar
201306, Uttar Pradesh, India.
The treatment measures of malignant carcinomas are most important for human
health. In recent years the use of targeted therapy based on small molecule
compounds and identical immunoglobulin has been the most frequently used tool to
combat cancerous cells. But there are still several limitations in their
clinical development and applications, including their ability to bind multiple
molecular target sites, both cell surface receptors and intracellular proteins,
promoting a greater risk of toxicity. PROTAC is a novel technology that
maintains a balance between protein synthesis and degradation and uses molecules
instead of conventional enzyme inhibitors, containing two active domains and a
linker to destroy unwanted selective protein (like kinase, skeleton protein and
regulatory protein). PROTACs are heterobifunctional nano molecules with a size
range of about 10 nanometres that eliminate the protein complexes formed by
protein-protein interaction through large and flat surfaces generally defined as
"undruggable" in conventional drug delivery systems, which include around 85% of
proteins present in humans, suggesting their wide application in the field of
drug development. Such peptide-based PROTACs have successfully shown targets'
destruction in cultured cells (e.g., MetAP-2, and FKBP12F36V, receptors for
estrogens and androgen). However, some obstacles prevent this technology from
transferring from the laboratory to its actual clinical utility, such as
delivery system and bioavailability. The scope of the presented review is to
give an overview of novel PROTAC technology with its limitations, advantages,
mechanism of action, and development of photocontrolled PROTACs and to summarize
its futuristic approach to targeting proteins in cancer cells.
Copyright© Bentham Science Publishers; For any queries, please email at
[email protected].
DOI: 10.2174/1570163820666221031124612
PMID: 36321238 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34100597 | 1. J Am Chem Soc. 2021 Jun 16;143(23):8902-8910. doi: 10.1021/jacs.1c03852. Epub
2021 Jun 8.
TF-PROTACs Enable Targeted Degradation of Transcription Factors.
Liu J(1), Chen H(2), Kaniskan HÜ(2), Xie L(3), Chen X(3), Jin J(2), Wei W(1).
Author information:
(1)Department of Pathology, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, Massachusetts 02215, United States.
(2)Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological
Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of
Medicine at Mount Sinai, New York, New York 10029, United States.
(3)Department of Biochemistry and Biophysics, University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Transcription factors (TFs) represent a major class of therapeutic targets for
the treatment of human diseases including cancer. Although the biological
functions and even crystal structures of many TFs have been clearly elucidated,
there is still no viable approach to target the majority of TFs, thus rendering
them undruggable for decades. PROTACs (proteolysis targeting chimeras) emerge as
a powerful class of therapeutic modalities, which rely on induced
protein-protein interactions between the proteins of interest (POIs) and E3
ubiquitin ligases to aid the degradation of POIs by the ubiquitin-proteasome
system (UPS). Here, we report the development of a platform termed TF-PROTAC,
which links an DNA oligonucleotide to an E3 ligase ligand via a click reaction,
to selectively degrade the TF of interest. The selectivity of these TF-PROTACs
depends on the DNA oligonucleotides utilized that can be specific to the TFs of
interest. We have developed two series of VHL-based TF-PROTACs, NF-κB-PROTAC
(dNF-κB) and E2F-PROTAC (dE2F), which effectively degrade endogenous p65 and
E2F1 proteins in cells, respectively, and subsequently display superior
antiproliferative effects in cells. Collectively, our results suggest that
TF-PROTACs provide a generalizable platform to achieve selective degradation of
TFs and a universal strategy for targeting most "undruggable" TFs.
DOI: 10.1021/jacs.1c03852
PMCID: PMC8225582
PMID: 34100597 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare the following competing
financial interest(s): W.W. is a co-founder and stockholder of the Rekindle
Thera-peutics. J.J. is a co-founder, equity shareholder and consultant of
Cullgen, Inc. The Jin laboratory received research funds from Celgene
Corporation, Levo Therapeutics, and Cullgen, Inc. All other authors declare no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35410300 | 1. Mol Cancer. 2022 Apr 11;21(1):99. doi: 10.1186/s12943-021-01434-3.
Proteolysis-targeting chimeras (PROTACs) in cancer therapy.
Li X(#)(1)(2), Pu W(#)(1), Zheng Q(1), Ai M(1), Chen S(3), Peng Y(4).
Author information:
(1)Laboratory of Molecular Oncology, Frontiers Science Center for
Disease-related Molecular Network, National Clinical Research Center for
Geriatrics, West China Hospital, Sichuan University, Chengdu, 610064, China.
(2)State Key Laboratory of Oral Diseases, National Clinical Research Center for
Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology,
Sichuan University, Chengdu, 610064, China.
(3)State Key Laboratory of Oral Diseases, National Clinical Research Center for
Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology,
Sichuan University, Chengdu, 610064, China. [email protected].
(4)Laboratory of Molecular Oncology, Frontiers Science Center for
Disease-related Molecular Network, National Clinical Research Center for
Geriatrics, West China Hospital, Sichuan University, Chengdu, 610064, China.
[email protected].
(#)Contributed equally
Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted
protein degradation. A bifunctional PROTAC molecule with two covalently-linked
ligands recruits target protein and E3 ubiquitin ligase together to trigger
proteasomal degradation of target protein by the ubiquitin-proteasome system.
PROTAC has emerged as a promising approach for targeted therapy in various
diseases, particularly in cancers. In this review, we introduce the principle
and development of PROTAC technology, as well as the advantages of PROTACs over
traditional anti-cancer therapies. Moreover, we summarize the application of
PROTACs in targeting critical oncoproteins, provide the guidelines for the
molecular design of PROTACs and discuss the challenges in the targeted
degradation by PROTACs.
© 2022. The Author(s).
DOI: 10.1186/s12943-021-01434-3
PMCID: PMC8996410
PMID: 35410300 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/30427680 | 1. J Am Chem Soc. 2018 Dec 5;140(48):16428-16432. doi: 10.1021/jacs.8b10320. Epub
2018 Nov 19.
Enhancing Antiproliferative Activity and Selectivity of a FLT-3 Inhibitor by
Proteolysis Targeting Chimera Conversion.
Burslem GM(1), Song J(1), Chen X(2), Hines J(1), Crews CM(1)(3).
Author information:
(1)Department of Molecular, Cellular and Developmental Biology , Yale University
, New Haven , Connecticut 06511 , United States.
(2)Arvinas Inc. , New Haven , Connecticut 06511 , United States.
(3)Departments of Chemistry and Pharmacology , Yale University , New Haven ,
Connecticut 06520 , United States.
The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid
leukemia; however, current small molecule inhibitors suffer from limited
efficacy in the clinic. Conversion of a FLT-3 inhibitor (quizartinib) into a
proteolysis targeting chimera (PROTAC) results in a compound that induces
degradation of FLT-3 ITD mutant at low nanomolar concentrations. Furthermore,
the PROTAC is capable of inhibiting cell growth more potently than the warhead
alone while inhibiting fewer off-target kinases. This enhanced antiproliferative
activity occurs, despite a slight reduction in the PROTAC's kinase inhibitory
activity, via an increased level of apoptosis induction suggesting nonkinase
roles for the FLT-3 ITD protein. Additionally, the PROTAC is capable of inducing
FLT-3 ITD degradation in vivo. These results suggest that degradation of FLT-3
ITD may provide a useful method for therapeutic intervention.
DOI: 10.1021/jacs.8b10320
PMID: 30427680 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18752944 | 1. Bioorg Med Chem Lett. 2008 Nov 15;18(22):5904-8. doi:
10.1016/j.bmcl.2008.07.114. Epub 2008 Jul 31.
Targeted intracellular protein degradation induced by a small molecule: En route
to chemical proteomics.
Schneekloth AR(1), Pucheault M, Tae HS, Crews CM.
Author information:
(1)Department of Chemistry, Yale University, PO Box 208103, New Haven, CT
06520-8103, USA.
We have developed a heterobifunctional all-small molecule PROTAC (PROteolysis
TArgeting Chimera) capable of inducing proteasomal degradation of the androgen
receptor. This cell permeable PROTAC consists of a non-steroidal androgen
receptor ligand (SARM) and the MDM2 ligand known as nutlin, connected by a
PEG-based linker. The SARM-nutlin PROTAC recruits the androgen receptor to MDM2,
which functions as an E3 ubiquitin ligase. This leads to the ubiquitination of
the androgen receptor, and its subsequent degradation by the proteasome. Upon
treatment of HeLa cells with 10microM PROTAC for 7h, we were able to observe a
decrease in androgen receptor levels. This degradation is proteasome dependent,
as it is mitigated in cells pre-treated with 10microM epoxomicin, a specific
proteasome inhibitor. These results have implications for the potential study
and treatment of various cancers with increased androgen receptor levels.
DOI: 10.1016/j.bmcl.2008.07.114
PMCID: PMC3175619
PMID: 18752944 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25305486 | 1. Biochem Biophys Res Commun. 2014 Oct 31;453(4):735-40. doi:
10.1016/j.bbrc.2014.10.006. Epub 2014 Oct 8.
Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of
the hepatitis B virus.
Montrose K(1), Krissansen GW(2).
Author information:
(1)Department of Molecular Medicine & Pathology, Faculty of Medical and Health
Sciences, University of Auckland, Auckland, New Zealand.
(2)Department of Molecular Medicine & Pathology, Faculty of Medical and Health
Sciences, University of Auckland, Auckland, New Zealand. Electronic address:
[email protected].
The X-protein of the hepatitis B virus (HBV) is essential for virus infection
and contributes to the development of HBV-induced hepatocellular carcinoma
(HCC), a disease which causes more than one million deaths each year. Here we
describe the design of a novel PROTAC (proteolysis targeting chimeric molecule)
capable of simultaneously inducing the degradation of the X-protein, and
antagonizing its function. The PROTAC was constructed by fusing the N-terminal
oligomerization and C-terminal instability domains of the X-protein to each
other, and rendering them cell-permeable by the inclusion of a polyarginine
cell-penetrating peptide (CPP). It was predicted that the oligomerization domain
would bind the X-protein, and that the instability domain would cause the
X-protein to be targeted for proteasomal degradation. Addition of the PROTAC to
HepG2 liver cancer cells, engineered to express full-length and C-terminally
truncated forms of the X-protein, resulted in the degradation of both forms of
the X-protein. A cell-permeable stand-alone form of the oligomerization domain
was taken up by HepG2 cells, and acted as a dominant-negative inhibitor, causing
inhibition of X-protein-induced apoptosis. In summary, the PROTAC described here
induces the degradation of the X-protein, and antagonizes its function, and
warrants investigation in a preclinical study for its ability to prevent or
treat HBV infection and/or the development of HCC.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bbrc.2014.10.006
PMID: 25305486 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31064868 | 1. Mol Cancer Ther. 2019 Jul;18(7):1302-1311. doi: 10.1158/1535-7163.MCT-18-1129.
Epub 2019 May 7.
Acquired Resistance to BET-PROTACs (Proteolysis-Targeting Chimeras) Caused by
Genomic Alterations in Core Components of E3 Ligase Complexes.
Zhang L(1), Riley-Gillis B(2), Vijay P(2), Shen Y(1).
Author information:
(1)Oncology Discovery, AbbVie Inc., North Chicago, Illinois. [email protected]
[email protected].
(2)Genomic Research Center, AbbVie Inc., North Chicago, Illinois.
Proteolysis-targeting chimeras (PROTAC) are bifunctional molecules that hijack
endogenous E3 ubiquitin ligases to induce ubiquitination and subsequent
degradation of protein of interest. Recently, it has been shown that PROTACs
with robust in vitro and in vivo activities and, in some cases, drug-like
pharmaceutical properties can be generated using small-molecule ligands for the
E3 ligases VHL and CRBN. These findings stoked tremendous enthusiasm on using
PROTACs for therapeutics development. Innate and acquired drug resistance often
underlies therapeutic failures, particularly for cancer therapy. With the PROTAC
technology progressing rapidly toward therapeutic applications, it would be
important to understand whether and how resistance to these novel agents may
emerge. Using BET-PROTACs as a model system, we demonstrate that resistance to
both VHL- and CRBN-based PROTACs can occur in cancer cells following chronic
treatment. However, unlike what was often observed for many targeted
therapeutics, resistance to BET-PROTACs did not result from secondary mutations
that affect compound binding to the target. In contrast, acquired resistance to
both VHL- and CRBN-based BET-PROTACs was primarily caused by genomic alterations
that compromise core components of the relevant E3 ligase complexes.
©2019 American Association for Cancer Research.
DOI: 10.1158/1535-7163.MCT-18-1129
PMID: 31064868 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35948047 | 1. Biochemistry. 2023 Feb 7;62(3):645-656. doi: 10.1021/acs.biochem.2c00288. Epub
2022 Aug 10.
Comprehensive Transcriptomic Analysis of Novel Class I HDAC Proteolysis
Targeting Chimeras (PROTACs).
Baker IM(1), Smalley JP(2), Sabat KA(1), Hodgkinson JT(2), Cowley SM(1).
Author information:
(1)Department of Molecular and Cell Biology, University of Leicester, Leicester
LE1 7RH, U.K.
(2)Leicester Institute of Structural and Chemical Biology, School of Chemistry,
University of Leicester, Leicester LE1 7RH, U.K.
The class I histone deacetylase (HDAC) enzymes;HDAC1,2 and 3 form the catalytic
engine of at least seven structurally distinct multiprotein complexes in cells.
These molecular machines play a vital role in the regulation of chromatin
accessibility and gene activity via the removal of acetyl moieties from lysine
residues within histone tails. Their inhibition via small molecule inhibitors
has beneficial effects in a number of disease types, including the clinical
treatment of hematological cancers. We have previously reported a library of
proteolysis targeting chimeras (PROTACs) incorporating a benzamide-based HDAC
ligand (from CI-994), with an alkyl linker and ligand for the von Hippel-Lindau
(VHL) E3 ubiquitin ligase that degrade HDAC1-3 at submicromolar concentrations.
Here we report the addition of two novel PROTACs (JPS026 and JPS027), which
utilize a ligand for the cellular inhibitor of apoptosis (IAP) family of E3
ligases. We found that both VHL (JPS004)- and IAP (JPS026)-based PROTACs degrade
HDAC1-3 and induce histone acetylation to a similar degree. However, JPS026 is
significantly more potent at inducing cell death in HCT116 cells than is JPS004.
RNA sequencing analysis of PROTAC-treated HCT116 cells showed a distinct gene
expression signature in which cell cycle and DNA replication machinery are
repressed. Components of the mTORC1 and -2 complexes were also reduced, leading
to an increase in FOXO3 and downstream target genes that regulate autophagy and
apoptosis. In summary, a novel combination of HDAC and IAP ligands generates a
PROTAC with a potent ability to stimulate apoptosis and differential gene
expression in human cancer cells.
DOI: 10.1021/acs.biochem.2c00288
PMCID: PMC9910044
PMID: 35948047 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare the following competing
financial interest(s): J.P.S., J.T.H., and S.M.C. are the inventors on PCT
patent application WO2021148811A1, HDAC Degrader. |
http://www.ncbi.nlm.nih.gov/pubmed/35500825 | 1. Cancer Lett. 2022 Jul 28;539:215716. doi: 10.1016/j.canlet.2022.215716. Epub
2022 Apr 30.
Proteolysis-targeting chimeras: A promising technique in cancer therapy for
gaining insights into tumor development.
Lv M(1), Hu W(1), Zhang S(1), He L(1), Hu C(2), Yang S(3).
Author information:
(1)Department of Gastroenterology, Xinqiao Hospital, Third Military Medical
University, Chongqing, 400037, China.
(2)Department of Gastroenterology, Xinqiao Hospital, Third Military Medical
University, Chongqing, 400037, China. Electronic address: [email protected].
(3)Department of Gastroenterology, Xinqiao Hospital, Third Military Medical
University, Chongqing, 400037, China. Electronic address:
[email protected].
Proteolysis-targeting chimeras (PROTACs) are small molecules that specifically
link E3 ubiquitin ligases to proteins of interest to mediate targeted
ubiquitination and degradation. PROTACs are advantageous since they can target
undruggable proteins with multiple domains, particularly those with smooth
surfaces that lack a common binding domain for small-molecule inhibitors (SMIs).
This review provides an overview of PROTAC technology and third-generation
PROTAC development. We focused on designing and executing the most recent
clinical trials involving PROTACs in cancer therapy. Additionally, we summarized
novel findings regarding the mechanisms and signaling pathways involved in
cancer development, such as the scaffolding function of certain proteins ignored
by traditional SMIs and several recognized oncoproteins that participate in
novel signaling pathways. We also discussed strategies for enhancing PROTAC
antitumor activity and specificity.
Copyright © 2022 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.canlet.2022.215716
PMID: 35500825 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33081540 | 1. Expert Opin Ther Pat. 2021 Jan;31(1):1-24. doi: 10.1080/13543776.2021.1840553.
Epub 2021 Jan 11.
The therapeutic potential of PROTACs.
Benowitz AB(1), Jones KL(1), Harling JD(1).
Author information:
(1)Medicine Design, GlaxoSmithKline , Stevenage, UK.
INTRODUCTION: PROTACs represent a novel class of heterobifunctional molecules
that simultaneously bind to a target protein and to an E3 ligase complex,
resulting in the transfer of ubiquitin and initiating a process ultimately
causing the proteasomal degradation of the target protein. This mechanism of
action imbues PROTACs with the ability to modulate target biology in unique ways
compared to inhibitors, and the development of PROTACs as therapeutic agents is
expected to result in new medicines to treat multiple diseases.
AREAS COVERED: This review includes published PCT (WO) patent applications
covering January 2013 through June 2020. Only English-language patent
applications with exemplified PROTACs reported to degrade a target protein(s)
were deemed in scope, and the definition of 'PROTAC' was restricted to a
bifunctional molecule which contains a discrete binding element for a specific
degradation target(s), as well as a separate discrete E3 ligase-binding moiety.
EXPERT OPINION: Delivering on the enormous potential of PROTACs will require the
development of PROTAC medicines that are differentiated from traditional
small-molecule inhibitors. The modular composition of PROTACs affords both
opportunities and challenges in securing robust intellectual property, and we
envision that requirements for novelty are likely to evolve as this area
matures.
DOI: 10.1080/13543776.2021.1840553
PMID: 33081540 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16338398 | 1. Methods Enzymol. 2005;399:833-47. doi: 10.1016/S0076-6879(05)99054-X.
Chimeric molecules to target proteins for ubiquitination and degradation.
Sakamoto KM(1).
Author information:
(1)Department of Pediatrics, Division of Hematology- Oncology Department of
Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles,
California, USA.
Protein degradation is one of the tactics used by the cell for irreversibly
inactivating proteins. In eukaryotes, ATP-dependent protein degradation in the
cytoplasm and nucleus is carried out by the 26S proteasome. Most proteins are
targeted to the 26S proteasome by covalent attachment of a multiubiquitin chain.
A key component of the enzyme cascade that results in attachment of the
multiubiquitin chain to the target or labile protein is the ubiquitin ligase
that controls the specificity of the ubiquitination reaction. Defects in
ubiquitin-dependent proteolysis have been shown to result in a variety of human
diseases, including cancer, neurodegenerative diseases, and metabolic disorders.
The SCF (Skp1-Cullin-F-box-Hrt1) complex is a heteromeric ubiquitin ligase that
multiubiquitinates proteins important for signal transduction and cell cycle
progression. A technology was developed known as Protac (Proteolysis Targeting
Chimeric Molecule) that acts as a bridge, bringing together the SCF ubiquitin
ligase with a protein target, resulting in its ubiquitination and degradation.
The Protac contains an SCF-binding peptide moiety at one end that is recognized
by SCF that is chemically linked to the binding partner or ligand of the target
protein. The first demonstration of the efficacy of Protac technology was the
successful recruitment, ubiquitination, and degradation of the protein
methionine aminopeptidase-2 (MetAP-2) through a covalent interaction between
MetAP-2 and Protac. Subsequently, we demonstrated that Protacs could effectively
ubiquitinate and degrade cancer-promoting proteins (estrogen and androgen
receptors) through noncovalent interactions in vitro and in cells. Finally,
cell-permeable Protacs can also promote the degradation of proteins in cells.
This chapter includes experiments to test the ability of Protacs to target
proteins in vitro and in cells.
DOI: 10.1016/S0076-6879(05)99054-X
PMID: 16338398 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34560429 | 1. Eur J Med Chem. 2021 Dec 15;226:113849. doi: 10.1016/j.ejmech.2021.113849.
Epub 2021 Sep 20.
AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and
noise-induced hearing loss.
Hati S(1), Zallocchi M(1), Hazlitt R(2), Li Y(1), Vijayakumar S(1), Min J(2),
Rankovic Z(2), Lovas S(1), Zuo J(3).
Author information:
(1)Department of Biomedical Sciences, School of Medicine, Creighton University,
Omaha, NE, 68178, USA.
(2)Department of Chemical Biology & Therapeutics, St. Jude Children's Research
Hospital, Memphis, TN, 38105, USA.
(3)Department of Biomedical Sciences, School of Medicine, Creighton University,
Omaha, NE, 68178, USA. Electronic address: [email protected].
Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the
treatment of hearing loss and cancer. Previously, we identified AZD5438 and
AT7519-7 as potent inhibitors of CDK2, however, they also targeted additional
kinases, leading to unwanted toxicities. Proteolysis Targeting Chimeras
(PROTACs) are a new promising class of small molecules that can effectively
direct specific proteins to proteasomal degradation. Herein we report the
design, synthesis, and characterization of PROTACs of AT7519-7 and AZD5438 and
the identification of PROTAC-8, an AZD5438-PROTAC, that exhibits selective,
partial CDK2 degradation. Furthermore, PROTAC-8 protects against cisplatin
ototoxicity and kainic acid excitotoxicity in zebrafish. Molecular dynamics
simulations reveal the structural requirements for CDK2 degradation. Together,
PROTAC-8 is among the first-in-class PROTACs with in vivo therapeutic activities
and represents a new lead compound that can be further developed for better
efficacy and selectivity for CDK2 degradation against hearing loss and cancer.
Copyright © 2021 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.ejmech.2021.113849
PMCID: PMC8608744
PMID: 34560429 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper. |
http://www.ncbi.nlm.nih.gov/pubmed/30672516 | 1. Chem Commun (Camb). 2019 Feb 5;55(12):1821-1824. doi: 10.1039/c8cc09541h.
PROTAC-mediated crosstalk between E3 ligases.
Steinebach C (1), Kehm H , Lindner S , Vu LP , Köpff S , López Mármol Á , Weiler
C , Wagner KG , Reichenzeller M , Krönke J , Gütschow M .
Author information:
(1)Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An
der Immenburg 4, 53121 Bonn, Germany. [email protected].
Small-molecule heterobifunctional degraders can effectively control protein
levels and are useful research tools. We assembled proteolysis targeting
chimeras (PROTACs) from a cereblon (CRBN) and a von-Hippel-Lindau (VHL) ligase
ligand and demonstrated a PROTAC-induced heterodimerization of the two E3
ligases leading to unidirectional and efficient degradation of CRBN.
DOI: 10.1039/c8cc09541h
PMID: 30672516 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31708096 | 1. Biochem Biophys Res Commun. 2020 Jan 22;521(4):833-839. doi:
10.1016/j.bbrc.2019.11.007. Epub 2019 Nov 7.
Protein targeting chimeric molecules specific for dual bromodomain 4 (BRD4) and
Polo-like kinase 1 (PLK1) proteins in acute myeloid leukemia cells.
Mu X(1), Bai L(2), Xu Y(2), Wang J(3), Lu H(4).
Author information:
(1)Department of Central Laboratory, China-Japan Union Hospital, Jilin
University, Changchun, China.
(2)College of Pharmacy, Jilin University, Changchun, China.
(3)School of Science, China Pharmaceutical University, Nanjing, China.
(4)College of Pharmacy, Jilin University, Changchun, China. Electronic address:
[email protected].
Proteolysis targeting chimeras (PROTACs) are hetero-bifunctional molecules that
could simultaneously bind to the target protein and the E3 ubiquitin ligase,
thereby leading to selective degradation of the target protein. Polo-like kinase
1 (PLK1) and bromodomain 4 (BRD4) are both attractive therapeutic targets in
acute myeloid leukemia (AML). Here, we developed a small-molecule BRD4 and PLK1
degrader HBL-4 based on PROTAC technology, which leads to fast, efficient, and
prolonged degradation of BRD4 and PLK1 in MV4-11 cells tested in vitro and vivo,
and potent anti-proliferation and BRD4 and PLK1 degradation ability in human
acute leukemia MOLM-13 and KG1 cells. Meanwhile, HBL-4 more effectively
suppresses c-Myc levels than inhibitor BI2536, resulting in more effective
inducing apoptosis activity in MV4-11 cells. At the same time, HBL-4 induced
dramatically improved efficacy in the MV4-11 tumor xenograft model as compared
with BI2536. This study is, to our knowledge, the first reports about dual PLK1
and BRD4 degraders, which potentially represents an important therapeutic
advance in the treatment of cancer.
Copyright © 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bbrc.2019.11.007
PMID: 31708096 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33406191 | 1. Chem Commun (Camb). 2021 Jan 25;57(8):1026-1029. doi: 10.1039/d0cc05395c. Epub
2021 Jan 6.
Traceless Staudinger ligation enabled parallel synthesis of proteolysis
targeting chimera linker variants.
Bemis TA (1), La Clair JJ , Burkart MD .
Author information:
(1)Department of Chemistry and Biochemistry, UC San Diego, 9500 Gilman Drive, La
Jolla, CA 92093-0358, USA. [email protected].
A parallel, one-pot assembly approach to proteolysis targeting chimeras
(PROTACs) is demonstrated utilizing activated esters generated in situ, and
traceless Staudinger ligation chemistry. The method described allows for rapid
structure-activity relationship studies of PROTAC linker variants. Two
previously studied systems, cereblon and BRD4 degraders, are examined as test
cases for the synthetic method. The two related strategies to assemble PROTAC
linker variants discussed can accommodate the chromotographic separations
capabilities of labs of many sizes and incorporates commercially available
degrader building blocks, thereby easing synthetic entry into PROTAC chemical
space.
DOI: 10.1039/d0cc05395c
PMCID: PMC7962863
PMID: 33406191
Conflict of interest statement: Conflicts of interest There are no conflicts to
declare. |
http://www.ncbi.nlm.nih.gov/pubmed/34081921 | 1. Cell Chem Biol. 2021 Oct 21;28(10):1528-1538.e4. doi:
10.1016/j.chembiol.2021.05.005. Epub 2021 Jun 2.
Native mass spectrometry and gas-phase fragmentation provide rapid and in-depth
topological characterization of a PROTAC ternary complex.
Song JH(1), Wagner ND(1), Yan J(1), Li J(2), Huang RY(2), Balog AJ(2), Newitt
JA(2), Chen G(2), Gross ML(3).
Author information:
(1)Department of Chemistry, Washington University in St. Louis, St. Louis, MO
63130, USA.
(2)Bristol Myers Squibb Company, Research and Early Development, Princeton, NJ
08543, USA.
(3)Department of Chemistry, Washington University in St. Louis, St. Louis, MO
63130, USA. Electronic address: [email protected].
Proteolysis-targeting chimeras (PROTACs) represent a new direction in
small-molecule therapeutics whereby a heterobifunctional linker to a protein of
interest (POI) induces its ubiquitination-based proteolysis by recruiting an E3
ligase. Here, we show that charge reduction, native mass spectrometry, and
gas-phase activation methods combine for an in-depth analysis of a PROTAC-linked
ternary complex. Electron capture dissociation (ECD) of the intact
POI-PROTAC-VCB complex (a trimeric subunit of an E3 ubiquitin ligase) promotes
POI dissociation. Collision-induced dissociation (CID) causes elimination of the
nonperipheral PROTAC, producing an intact VCB-POI complex not seen in solution
but consistent with PROTAC-induced protein-protein interactions. In addition, we
used ion mobility spectrometry (IMS) and collisional activation to identify the
source of this unexpected dissociation. Together, the evidence shows that this
integrated approach can be used to screen for ternary complex formation and
PROTAC-protein contacts and may report on PROTAC-induced protein-protein
interactions, a characteristic correlated with PROTAC selectivity and efficacy.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.chembiol.2021.05.005
PMCID: PMC8592818
PMID: 34081921 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests Michael L. Gross is an
unpaid member of the scientific advisory boards of Protein Metrics Inc. and Gen
Next Technologies, two companies pursuing ideas in structural mass spectrometry. |
http://www.ncbi.nlm.nih.gov/pubmed/36139095 | 1. Biomolecules. 2022 Sep 7;12(9):1257. doi: 10.3390/biom12091257.
Recent Advances of Degradation Technologies Based on PROTAC Mechanism.
Xiao M(1)(2), Zhao J(1)(2), Wang Q(3), Liu J(4), Ma L(1).
Author information:
(1)Cancer Institute of The Affiliated Hospital, Qingdao University, Qingdao
266071, China.
(2)School of Basic Medicine, Qingdao University, Qingdao 266071, China.
(3)Oncology Department, Shandong Second Provincial General Hospital, Jinan
250022, China.
(4)Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao
266071, China.
PROTAC (proteolysis-targeting chimeras), which selectively degrades target
proteins, has become the most popular technology for drug development in recent
years. Here, we introduce the history of PROTAC, and summarize the recent
advances in novel types of degradation technologies based on the PROTAC
mechanism, including TF-PROTAC, Light-controllable PROTAC, PhosphoTAC, LYTAC,
AUTAC, ATTEC, CMA, RNA-PROTAC and RIBOTACs. In addition, the clinical progress,
current challenges and future prospects of degradation technologies based on
PROTAC mechanism are discussed.
DOI: 10.3390/biom12091257
PMCID: PMC9496103
PMID: 36139095 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34240523 | 1. Angew Chem Int Ed Engl. 2021 Oct 18;60(43):23299-23305. doi:
10.1002/anie.202107347. Epub 2021 Aug 11.
Aptamer-PROTAC Conjugates (APCs) for Tumor-Specific Targeting in Breast Cancer.
He S(1), Gao F(1), Ma J(2), Ma H(2), Dong G(2), Sheng C(2).
Author information:
(1)Institute of Translational Medicine, Shanghai University, Shanghai, 200444,
China.
(2)School of Pharmacy, Second Military Medical University, Shanghai, 200433,
China.
Development of proteolysis targeting chimeras (PROTACs) is emerging as a
promising strategy for targeted protein degradation. However, the drug
development using the heterobifunctional PROTAC molecules is generally limited
by poor membrane permeability, low in vivo efficacy and indiscriminate
distribution. Herein an aptamer-PROTAC conjugation approach was developed as a
novel strategy to improve the tumor-specific targeting ability and in vivo
antitumor potency of conventional PROTACs. As proof of concept, the first
aptamer-PROTAC conjugate (APC) was designed by conjugating a BET-targeting
PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared
with the unmodified BET PROTAC, the designed molecule (APR) showed improved
tumor targeting ability in a MCF-7 xenograft model, leading to enhanced in vivo
BET degradation and antitumor potency and decreased toxicity. Thus, the APC
strategy may pave the way for the design of tumor-specific targeting PROTACs and
have broad applications in the development of PROTAC-based drugs.
© 2021 Wiley-VCH GmbH.
DOI: 10.1002/anie.202107347
PMID: 34240523 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32770212 | 1. Adv Nutr. 2020 Nov 16;11(6):1405-1413. doi: 10.1093/advances/nmaa089.
The "Virtual Digital Twins" Concept in Precision Nutrition.
Gkouskou K(1)(2), Vlastos I(1), Karkalousos P(3), Chaniotis D(3), Sanoudou
D(4)(5)(6), Eliopoulos AG(1)(5)(6).
Author information:
(1)Department of Biology, School of Medicine, National and Kapodistrian
University of Athens, Athens, Greece.
(2)Embiodiagnostics, Biology Research Company, Heraklion, Crete, Greece.
(3)Department of Biomedical Sciences, University of West Attica, Athens, Greece.
(4)Clinical Genomics and Pharmacogenomics Unit, 4th Department of Internal
Medicine, School of Medicine, National and Kapodistrian University of Athens,
Athens, Greece.
(5)Center for New Biotechnologies and Precision Medicine, School of Medicine,
National and Kapodistrian University of Athens, Athens, Greece.
(6)Center of Basic Research, Biomedical Research Foundation of the Academy of
Athens, Athens, Greece.
Nutritional and lifestyle changes remain at the core of healthy aging and
disease prevention. Accumulating evidence underscores the impact of genetic,
metabolic, and host gut microbial factors on individual responses to nutrients,
paving the way for the stratification of nutritional guidelines. However,
technological advances that incorporate biological, nutritional, lifestyle, and
health data at an unprecedented scale and depth conceptualize a future where
preventative dietary interventions will exceed stratification and will be highly
individualized. We herein discuss how genetic information combined with
longitudinal metabolomic, immune, behavioral, and gut microbial parameters, and
bioclinical variables could define a digital replica of oneself, a "virtual
digital twin," which could serve to guide nutrition in a personalized manner.
Such a model may revolutionize the management of obesity and its comorbidities,
and provide a pillar for healthy aging.
Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.
DOI: 10.1093/advances/nmaa089
PMCID: PMC7666894
PMID: 32770212 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35661166 | 1. N Engl J Med. 2022 Aug 11;387(6):495-505. doi: 10.1056/NEJMoa2203478. Epub
2022 Jun 5.
Teclistamab in Relapsed or Refractory Multiple Myeloma.
Moreau P(1), Garfall AL(1), van de Donk NWCJ(1), Nahi H(1), San-Miguel JF(1),
Oriol A(1), Nooka AK(1), Martin T(1), Rosinol L(1), Chari A(1), Karlin L(1),
Benboubker L(1), Mateos MV(1), Bahlis N(1), Popat R(1), Besemer B(1),
Martínez-López J(1), Sidana S(1), Delforge M(1), Pei L(1), Trancucci D(1),
Verona R(1), Girgis S(1), Lin SXW(1), Olyslager Y(1), Jaffe M(1), Uhlar C(1),
Stephenson T(1), Van Rampelbergh R(1), Banerjee A(1), Goldberg JD(1), Kobos
R(1), Krishnan A(1), Usmani SZ(1).
Author information:
(1)From the Hematology Clinic, University Hospital Hôtel-Dieu, Nantes (P.M.),
Service d'Hématologie Clinique, Centre Hospitalier Lyon Sud, Pierre-Bénite
(L.K.), and Service d'Hématologie et Thérapie Cellulaire, Hôpital Bretonneau,
Centre Hospitalier Régional Universitaire, Tours (L.B.) - all in France;
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania,
Philadelphia (A.L.G.), and Janssen Research and Development, Spring House (R.V.,
S.G., S.X.W.L., C.U., T.S., A.B.) - both in Pennsylvania; the Department of
Hematology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam,
Cancer Center Amsterdam, Amsterdam (N.W.C.J.D.); Karolinska University Hospital
at Huddinge, Stockholm (H.N.); Clínica Universidad de Navarra, Centro de
Investigación Médica Aplicada, Centro de Investigación Biomédica en Red de
Cáncer (CIBERONC), Instituto de Investigación Sanitaria de Navarra, Pamplona
(J.F.S.-M.), Institut Català d'Oncologia and Institut Josep Carreras, Hospital
Germans Trias i Pujol, Badalona (A.O.), Hospital Clínic, August Pi i Sunyer
Biomedical Research Institute, University of Barcelona, Barcelona (L.R.),
University Hospital of Salamanca, Instituto de Investigación Biomédica de
Salamanca, Centro del Investigación del Cáncer, CIBERONC, Salamanca (M.-V.M.),
and Hematological Malignancies Clinical Research Unit, Hospital 12 de Octubre
Universidad Complutense, Centro Nacional de Investigaciones Oncológicas,
CIBERONC, Madrid (J.M.-L.) - all in Spain; Winship Cancer Institute, Emory
University, Atlanta (A.K.N.); the University of California, San Francisco, San
Francisco (T.M.), Stanford University School of Medicine, Stanford (S.S.), and
City of Hope Comprehensive Cancer Center, Duarte (A.K.) - all in California;
Mount Sinai School of Medicine (A.C.) and Memorial Sloan Kettering Cancer Center
(S.Z.U.) - both in New York; Arnie Charbonneau Cancer Institute, University of
Calgary, Calgary, AB, Canada (N.B.); Clinical Research Facility, National
Institute for Health Research University College London Hospitals, NHS
Foundation Trust, London (R.P.); the Department of Hematology, Oncology, and
Immunology, University of Tübingen, Tübingen, Germany (B.B.); the University of
Leuven, Leuven (M.D.), and Janssen Research and Development, Antwerp (Y.O.,
R.V.R.) - both in Belgium; Janssen Research and Development, Raritan, NJ (L.P.,
D.T., M.J., J.D.G., R.K.); and Levine Cancer Institute-Atrium Health, Charlotte,
NC (S.Z.U.).
Comment in
N Engl J Med. 2022 Aug 11;387(6):558-561. doi: 10.1056/NEJMe2209692.
N Engl J Med. 2022 Nov 3;387(18):1721. doi: 10.1056/NEJMc2211969.
N Engl J Med. 2022 Nov 3;387(18):1721-1722. doi: 10.1056/NEJMc2211969.
BACKGROUND: Teclistamab is a T-cell-redirecting bispecific antibody that targets
both CD3 expressed on the surface of T cells and B-cell maturation antigen
expressed on the surface of myeloma cells. In the phase 1 dose-defining portion
of the study, teclistamab showed promising efficacy in patients with relapsed or
refractory multiple myeloma.
METHODS: In this phase 1-2 study, we enrolled patients who had relapsed or
refractory myeloma after at least three therapy lines, including triple-class
exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38
antibody. Patients received a weekly subcutaneous injection of teclistamab (at a
dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of
0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response
(partial response or better).
RESULTS: Among 165 patients who received teclistamab, 77.6% had triple-class
refractory disease (median, five previous therapy lines). With a median
follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients
(39.4%) having a complete response or better. A total of 44 patients (26.7%)
were found to have no minimal residual disease (MRD); the MRD-negativity rate
among the patients with a complete response or better was 46%. The median
duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not
estimable). The median duration of progression-free survival was 11.3 months
(95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome
(in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%;
grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and
thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in
76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%),
including immune effector cell-associated neurotoxicity syndrome in 5 patients
(3.0%; all grade 1 or 2).
CONCLUSIONS: Teclistamab resulted in a high rate of deep and durable response in
patients with triple-class-exposed relapsed or refractory multiple myeloma.
Cytopenias and infections were common; toxic effects that were consistent with
T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and
Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and
NCT04557098.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2203478
PMCID: PMC10587778
PMID: 35661166 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36006441 | 1. Blood Adv. 2023 Feb 28;7(4):644-648. doi: 10.1182/bloodadvances.2022007625.
Effects of teclistamab and talquetamab on soluble BCMA levels in patients with
relapsed/refractory multiple myeloma.
Girgis S(1), Wang Lin SX(1), Pillarisetti K(1), Verona R(1), Vieyra D(1),
Casneuf T(2), Fink D(1), Miao X(1), Chen Y(1), Stephenson T(1), Banerjee A(1),
Hilder BW(1), Russell J(1), Infante J(1), Elsayed Y(1), Smit J(1), Goldberg
JD(1).
Author information:
(1)Janssen Research & Development, LLC, Spring House, PA.
(2)Janssen Research & Development, LLC, Beerse, Belgium.
DOI: 10.1182/bloodadvances.2022007625
PMCID: PMC9979748
PMID: 36006441 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest disclosure: D.F., Y.C., and
J.R. are former employees of Janssen Research & Development and may own
stock/stock options in Johnson & Johnson. The remaining authors are currently
employees of Janssen Research & Development and may own stock/stock options in
Johnson & Johnson. |
http://www.ncbi.nlm.nih.gov/pubmed/35749004 | 1. Target Oncol. 2022 Jul;17(4):433-439. doi: 10.1007/s11523-022-00893-y. Epub
2022 Jun 24.
Translational Modeling Predicts Efficacious Therapeutic Dosing Range of
Teclistamab for Multiple Myeloma.
Girgis S(1), Lin SXW(2), Pillarisetti K(2), Banerjee A(2), Stephenson T(2), Ma
X(2), Shetty S(2), Yang TY(2), Hilder BW(2), Jiao Q(2), Hanna B(2), Adams HC
3rd(2), Sun YN(2), Sharma A(3), Smit J(2), Infante JR(4), Goldberg JD(4),
Elsayed Y(2).
Author information:
(1)Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA.
[email protected].
(2)Janssen Research & Development, Spring House, PA, USA.
(3)Janssen Research & Development, Tokyo, Japan.
(4)Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA.
Erratum in
Target Oncol. 2022 Sep;17(5):609. doi: 10.1007/s11523-022-00904-y.
BACKGROUND: Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3
bispecific antibody, displayed potent T-cell-mediated cytotoxicity of multiple
myeloma cells in preclinical studies.
OBJECTIVE: A first-in-human, Phase I, dose escalation study (MajesTEC-1) is
evaluating teclistamab in patients with relapsed/refractory multiple myeloma.
PATIENTS AND METHODS: To estimate the efficacious therapeutic dosing range of
teclistamab, pharmacokinetic (PK) data following the first cycle doses in the
low-dose cohorts in the Phase I study were modeled using a 2-compartment model
and simulated to predict the doses that would have average and trough serum
teclistamab concentrations in the expected therapeutic range (between EC50 and
EC90 values from an ex vivo cytotoxicity assay).
RESULTS: The doses predicted to have average serum concentrations between the
EC50 and EC90 range were validated. In addition, simulations showed that weekly
intravenous and subcutaneous doses of 0.70 mg/kg and 0.72 mg/kg, respectively,
resulted in mean trough levels comparable to the maximum EC90. The most active
doses in the Phase I study were weekly intravenous doses of 0.27 and 0.72 mg/kg
and weekly subcutaneous doses of 0.72 and 1.5 mg/kg, with the weekly 1.5 mg/kg
subcutaneous doses selected as the recommended Phase II dose (RP2D). With active
doses, exposure was maintained above the mean EC90. All patients who responded
to the RP2D of teclistamab had exposure above the maximum EC90 in both serum and
bone marrow on cycle 3, Day 1 of treatment.
CONCLUSIONS: Our findings show that PK simulations of early clinical data
together with ex vivo cytotoxicity estimates can inform the identification of a
bispecific antibody's therapeutic range.
CLINICAL TRIAL REGISTRATION: NCT03145181, date of registration: May 9, 2017.
© 2022. The Author(s).
DOI: 10.1007/s11523-022-00893-y
PMCID: PMC9345835
PMID: 35749004 [Indexed for MEDLINE]
Conflict of interest statement: B. Hanna, H. Adams, S. Shetty, and Y. Sun were
employees of Johnson & Johnson during the completion of this work. All other
authors are current employees of Johnson & Johnson and may hold stock in Johnson
& Johnson. |
http://www.ncbi.nlm.nih.gov/pubmed/36352205 | 1. Drugs. 2022 Nov;82(16):1613-1619. doi: 10.1007/s40265-022-01793-1.
Teclistamab: First Approval.
Kang C(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. [email protected].
Teclistamab (TECVAYLI®), a bispecific antibody that targets CD3 and B cell
maturation antigen (BCMA), is being developed by Janssen Research and
Development for the treatment of relapsed or refractory multiple myeloma.
Teclistamab was recently granted conditional approval in the EU for the
treatment of adult patients with relapsed and refractory multiple myeloma who
have received three or more prior therapies (including an immunomodulatory
agent, a proteasome inhibitor and an anti-CD38 antibody) and have demonstrated
disease progression on the last therapy. Teclistamab was subsequently approved
in the US for the treatment of adult patients with relapsed or refractory
multiple myeloma who have received at least four prior lines of therapy
(including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38
antibody). This article summarizes the milestones in the development of
teclistamab leading to this first approval for relapsed or refractory multiple
myeloma.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01793-1
PMCID: PMC9646474
PMID: 36352205 [Indexed for MEDLINE]
Conflict of interest statement: During the peer review process the manufacturer
of the agent under review was offered an opportunity to comment on the article.
Changes resulting from any comments received were made by the authors on the
basis of scientific completeness and accuracy. Connie Kang is a salaried
employee of Adis International Ltd/Springer Nature, and declares no relevant
conflicts of interest. All authors contributed to the review and are responsible
for the article content. |
http://www.ncbi.nlm.nih.gov/pubmed/33896963 | 1. Gynakologe. 2021;54(5):341-356. doi: 10.1007/s00129-021-04787-4. Epub 2021 Apr
20.
[Intrahepatic cholestasis of pregnancy].
[Article in German]
Hagenbeck C(1), Pecks U(2), Lammert F(3), Hütten MAC(4), Borgmeier F(1), Fehm
T(1), Schleußner E(5), Maul H(6), Kehl S(7), Hamza A(8)(9), Keitel V(10).
Author information:
(1)Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf,
Moorenstraße 5, 40225 Düsseldorf, Deutschland.
(2)Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum
Schleswig-Holstein, Campus Kiel, Kiel, Deutschland.
(3)Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes,
Universität des Saarlandes, Homburg, Deutschland.
(4)Neonatologie, Maastricht Universitair Medisch Centrum+, Maastricht,
Niederlande.
(5)Klinik für Geburtsmedizin, Universität Jena, Jena, Deutschland.
(6)Frauenklinik, Asklepios Kliniken Barmbek, Wandsbek und Nord-Heidberg,
Hamburg, Deutschland.
(7)Frauenklinik, Universitätsklinikum Erlangen, Erlangen, Deutschland.
(8)Kantonsspital Baden, Baden, Schweiz.
(9)Klinikum für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin,
Universität des Saarlandes, Homburg, Deutschland.
(10)Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universität
Düsseldorf, Düsseldorf, Deutschland.
Intrahepatic cholestasis of pregnancy (ICP) is the most frequent
pregnancy-specific liver disease. It is characterized by pruritus and an
accompanying elevation of serum bile acid concentrations and/or alanine
aminotransferase (ALT), which are the key parameters in the diagnosis. Despite
good maternal prognosis, elevated bile acid concentration in maternal blood is
an influencing factor to advers fetal outcome. The ICP is associated with
increased rates of preterm birth, neonatal unit admission and stillbirth. This
is the result of acute fetal asphyxia as opposed to a chronic uteroplacental
insufficiency. Reliable monitoring or predictive tools (e.g. cardiotocography
(CTG) or ultrasound) that help to prevent advers events are yet to be explored.
Medicinal treatment with ursodeoxycholic acid (UDCA) does not demonstrably
reduce adverse perinatal outcomes but does improve pruritus and liver function
test results. Bile acid concentrations and gestational age should be used as
indications to determine delivery. There is a high risk of recurrence in
subsequent pregnancies.
Die Schwangerschaftscholestase („intrahepatic cholestasis of pregnancy“, ICP)
ist die häufigste schwangerschaftsspezifische Lebererkrankung. Das Leitsymptom
Juckreiz sowie eine begleitende Serumkonzentrationserhöhung von Gallensäuren
und/oder der Alaninaminotransferase (ALT) sind wegweisend in der
Diagnosestellung. Die mütterliche Prognose ist gut. Das fetale Outcome ist
abhängig von der Gallensäurenkonzentration. Die ICP ist dabei sowohl mit
Frühgeburt als auch mit intrauterinem Fruchttod (IUFT) assoziiert. Dieser ist
Folge einer akuten fetalen Asphyxie, nicht einer chronischen uteroplazentaren
Dysfunktion. Ein prädiktives Monitoring, z. B. durch Kardiotokographie (CTG)
oder Ultraschall gibt es nicht. Eine medikamentöse Therapie mit
Ursodeoxycholsäure (UDCA) bessert den Juckreiz, aber beeinflusst das fetale
Outcome nicht nachweislich. Eine Entbindungsindikation ist in Abhängigkeit von
Gallensäurenkonzentration und Gestationsalter gegeben. In Folgeschwangerschaften
besteht ein hohes Wiederholungsrisiko.
© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2021.
DOI: 10.1007/s00129-021-04787-4
PMCID: PMC8056200
PMID: 33896963 |
http://www.ncbi.nlm.nih.gov/pubmed/27530795 | 1. Zhongguo Dang Dai Er Ke Za Zhi. 2016 Aug;18(8):751-6. doi:
10.7499/j.issn.1008-8830.2016.08.016.
[Clinical feature and ATP8B1 mutation analysis of a patient with progressive
familial intrahepatic cholestasis type I].
[Article in Chinese]
Cheng Y(1), Guo L, Song YZ.
Author information:
(1)Department of Pediatrics, First Affiliated Hospital, Jinan University,
Guangzhou 510632, China. [email protected].
Progressive familial intrahepatic cholestasis type I (PFIC1) is an autosomal
recessive disorder caused by biallelic mutations of ATP8B1 gene, with
progressive cholestasis as the main clinical manifestation. This paper reports
the clinical and genetic features of a PFIC1 patient definitely diagnosed by
ATP8B1 genetic analysis. The patient, a boy aged 14 months, was referred to the
hospital with the complaint of jaundiced skin and sclera over 10 months. The
patient had been managed in different hospitals, but the therapeutic effects
were unsatisfactory due to undetermined etiology. On physical examination,
hepatosplenomegaly was discovered in addition to jaundice of the skin and
sclera. The liver was palpable 4 cm below the right subcostal margin and 2 cm
below the xiphoid while the spleen 2 cm below the left subcostal margin. The
liver function test revealed elevated levels of serum total bile acids,
bilirubin, and transaminases; however, the γ-glutamyl transferase level was
normal. The diagnosis was genetic cholestasis of undetermined origin. At the age
of 1 year and 8 months, a Roux-en-Y cholecystocolonic bypass operation was
performed, and thereafter the jaundice disappeared. At 5 years and 1 month, via
whole genome sequencing analysis and Sanger sequencing confirmation, the boy was
found to be a homozygote of mutation c.2081T>A(p.I694N) of ATP8B1 gene, and thus
PFIC1 was definitely diagnosed. The boy was followed up until he was 6 years,
and jaundice did not recur, but the long-term outcome remains to be observed.
进行性家族性肝内胆汁淤积症1型（PFIC1）是一种ATP8B1基因突变导致的以进行性胆汁淤积为主要临床表现的常染色体隐性遗传病。该文报道1例经ATP8B1突变分析证实的PFIC1患儿临床和遗传学特征。患儿为1岁2个月的男孩，因发现皮肤黄染10月余就诊。发病后先后在多家医院诊治，病因不详，疗效不佳。体查发现皮肤巩膜黄染，肝右肋下4cm，剑突下2cm，脾左肋下2cm可触及。肝功能检查发现血清胆汁酸、胆红素、转氨酶等均升高，而γ-谷氨酰转肽酶水平未见异常。诊断为遗传性胆汁淤积症，但病因不明。1岁8个月时经胆囊结肠Roux-en-Y吻合术，之后患儿黄疸迅速消退。5岁1个月时经全基因组测序及Sanger测序验证，发现患儿为ATP8B1基因突变c.2081T
> A（p.I694N）的纯合子，最终确诊为PFIC1。电话随访至6岁，黄疸未再反复，但远期预后有待观察。
DOI: 10.7499/j.issn.1008-8830.2016.08.016
PMCID: PMC7399514
PMID: 27530795 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10385057 | 1. J Gastroenterol Hepatol. 1999 Jun;14(6):515-8. doi:
10.1046/j.1440-1746.1999.01907.x.
Cholestasis of pregnancy.
McDonald JA(1).
Author information:
(1)Department of Gastroenterology, Wollongong Hospital, New South Wales,
Australia.
Cholestasis of pregnancy is the commonest liver disease unique to pregnancy and
is characterized by pruritus in the mother in late pregnancy, without any skin
rashes. This is accompanied by an elevation of the serum bile acids. Liver
function test abnormalities may occur. Abdominal pain is not a feature and liver
failure does not occur. The diagnosis is made by a suggestive history and
exclusion of other causes by the history, serology and an upper abdominal
ultrasound. All symptoms and signs should disappear within 4 weeks post-partum;
prolonged post-partum courses should prompt a search for other causes, such as
primary biliary cirrhosis. The syndrome is associated with a five-fold increased
incidence of stillbirth, intra-partum foetal distress and pre-term labour. The
reason is not clear and not predictable. The accepted management is induction or
delivery at 38 weeks, which has led to a reduction in poor foetal outcome.
Preliminary studies using ursodeoxycholic acid show symptomatic and biochemical
improvement in most women treated. There is also a suggestion of an improved
foetal outcome and treatment should be considered in women who present with the
condition earlier in pregnancy.
DOI: 10.1046/j.1440-1746.1999.01907.x
PMID: 10385057 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17163822 | 1. Clin Chem Lab Med. 2006;44(12):1453-6. doi: 10.1515/CCLM.2006.261.
Stone or stricture as a cause of extrahepatic cholestasis--do liver function
tests predict the diagnosis?
Karvonen J(1), Kairisto V, Grönroos JM.
Author information:
(1)Department of Surgery, University of Turku, Turku, Finland.
BACKGROUND: Cholestasis, roughly divided into intrahepatic and extrahepatic
forms, is a clinical challenge. Extrahepatic cholestasis, characterized by
dilated bile ducts, is caused by either a bile duct stone or stricture, with
stricture most often related to a malignancy. The aim of the present study was
to analyze the value of common liver function tests in separating patients with
malignant bile duct strictures from those with stones.
METHODS: All consecutive patients admitted for endoscopic retrograde
cholangiopancreatography (ERCP) were included in the study population if a bile
duct stricture related to a malignancy was found by ERCP (n=103) or if a bile
duct stone was successfully extracted during ERCP, thus confirming the diagnosis
of a stone (n=109). Plasma alkaline phosphatase, gamma-glutamyltransferase,
alanine aminotransferase and bilirubin values were determined in the morning
before ERCP.
RESULTS: Plasma bilirubin (p<0.001), alkaline phosphatase (p<0.001) and alanine
aminotransferase (p=0.040) levels were significantly higher in patients with
malignant bile duct strictures than in those with bile duct stones. In addition,
gamma-glutamyltransferase levels seemed to be higher in patients with malignant
strictures than in those with stones, although the difference did not reach
statistical significance (p=0.053). In receiver operating characteristic
analyses, bilirubin proved to be the best laboratory test in differentiating
patients (p=0.001 vs. alkaline phosphatase, p<0.001 vs. alanine aminotransferase
and p<0.001 vs. gamma-glutamyltransferase). With a plasma bilirubin cutoff value
of 145 micromol/L, four out of five patients were categorized correctly.
CONCLUSIONS: Plasma bilirubin seems to be the best liver function test in
distinguishing patients with malignant bile duct strictures from those with bile
duct stones. This routine test should receive more attention in clinical
decision-making than has previously been given.
DOI: 10.1515/CCLM.2006.261
PMID: 17163822 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/493809 | 1. Ric Clin Lab. 1979 Jan-Mar;9(1):1-4.
Serum bile acids (a new advance in the diagnosis of liver disease).
Demers LM.
Serum bile acid measurements now available by radioimmunoassay have proven to be
the most sensitive procedure developed to date to assess diseases of the
hepatobiliary system in both adult and pediatric liver disease. Their clinical
utility appears to hold particular promise in establishing the early diagnosis
of liver disease when conventional liver function test such as SGOT, alkaline
phosphatase, bilirubin and albumin are still normal. Serum bile acid
determinations have been shown to be particularly useful in the diagnosis of
alcoholic liver disease, drug-induced liver disease, viral hepatitis and
cholestasis of intra- and extrahepatic origin. In infants, serum bile acid
measurements can be used to establish the diagnosis of biliary atresia. When
serum bile acids are determined post-prandially, they are the most sensitive
indicator of liver dysfunction developed to date.
PMID: 493809 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9794902 | 1. Hepatology. 1998 Nov;28(5):1199-205. doi: 10.1002/hep.510280506.
Lipoprotein-X in patients with cirrhosis: its relationship to cholestasis and
hypercholesterolemia.
Sörös P(1), Böttcher J, Maschek H, Selberg O, Müller MJ.
Author information:
(1)Abteilung Gastroenterologie und Hepatologie, Medizinische Hochschule
Hannover, Hannover, Germany. [email protected]
Lipoprotein-X (Lp-X) is an abnormal low-density lipoprotein frequently found in
liver disease. It is regarded as the most sensitive and specific biochemical
parameter for the diagnosis of intra- and extrahepatic cholestasis. Moreover,
Lp-X is supposed to contribute to the development of hypercholesterolemia in
cholestatic liver disease, because it fails to inhibit de novo cholesterol
synthesis. This investigation will focus on the relationship between the
presence of Lp-X and serum lipid concentrations in cirrhosis. The significance
of Lp-X in the diagnosis of cholestasis, compared with alkaline phosphatase
(AP), gamma-glutamyl transferase (GGT), and bilirubin levels, will be assessed
as well. The present cross-sectional study includes 212 patients with
histopathologically proven cirrhosis. The detection of Lp-X and the
quantification of -, beta-, and pre-beta-cholesterol was based on agar gel
electrophoresis and polyanion precipitation. For the characterization of liver
function, the concentrations of albumin and bilirubin, the activities of liver
enzymes, and coagulation times were assessed. In a subgroup of 40 individuals,
liver biopsies were re-evaluated to confirm or exclude intrahepatic cholestasis.
As a result, there was no association between the appearance of Lp-X and total
cholesterol concentrations. While all patients with Lp-X showed intrahepatic
cholestasis (predictive value of the positive test = 1), only 16 of 28 patients
with cholestasis formed Lp-X (sensitivity = 0.57). The activities of AP and of
GGT, as well as the concentrations of bilirubin, were strongly elevated in most
patients, with and without cholestasis. The predictive values of AP, GGT, and
bilirubin were 0.77, 0.69, and 0.74 for the positive test and 0.5, 0, and 0.6
for the negative test, respectively. We conclude that Lp-X is not related to
hypercholesterolemia in cirrhosis. The positive, but not the negative, Lp-X test
has high predictive value for the diagnosis of cholestasis in cirrhosis. The
biochemical parameters traditionally used for the assessment of extrahepatic
cholestasis, AP, GGT, and bilirubin, do not support the diagnosis of
intrahepatic cholestasis caused by cirrhosis.
DOI: 10.1002/hep.510280506
PMID: 9794902 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7583073 | 1. QJM. 1995 Sep;88(9):603-7.
Pruritus of chronic cholestasis.
Raiford DS(1).
Author information:
(1)Division of Gastroenterology, Vanderbilt University School of Medicine,
Nashville, TN 37232-2279, USA.
Pruritus is a challenging clinical problem which often complicates chronic
cholestatic liver disease. For practical purposes, cholestasis may be defined as
impaired hepatocellular secretion of bile and is a feature of a wide variety of
liver diseases. Cholestasis is usually suspected clinically when a patient
presenting with jaundice or pruritus is found to have an elevation in serum
alkaline phosphatase activity disproportionate to increases in serum
aminotransferase levels. Early imaging by ultrasonography, computerized
tomography, or cholangiography is important to address the possibility of
remediable biliary tract obstruction. The majority of patients who develop
problematic pruritus due to chronic cholestasis will have one of several
diseases: primary biliary cirrhosis, primary sclerosing cholangitis,
drug-induced cholestasis, autoimmune chronic active hepatitis, or alcoholic
liver disease. Specific aetiological diagnosis is usually possible when history
and physical examination are complemented, as appropriate, by serological
testing, hepatobiliary imaging, and liver biopsy. This review does not address
issues in diagnosis, but concentrates upon the management of pruritus, a
potentially disabling complication of prolonged cholestasis.
PMID: 7583073 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34146512 | 1. Lancet Neurol. 2021 Jul;20(7):537-547. doi: 10.1016/S1474-4422(21)00043-0.
Safety and efficacy of pioglitazone for the delay of cognitive impairment in
people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study
and a phase 3, randomised, double-blind, placebo-controlled trial.
Burns DK(1), Alexander RC(2), Welsh-Bohmer KA(3), Culp M(2), Chiang C(4), O'Neil
J(5), Evans RM(2), Harrigan P(5), Plassman BL(3), Burke JR(6), Wu J(2), Lutz
MW(6), Haneline S(4), Schwarz AJ(2), Schneider LS(7), Yaffe K(8), Saunders
AM(4), Ratti E(2); TOMMORROW study investigators.
Collaborators: Aarsland D, Ackermann O, Agron-Figueroa J, Arnold T, Bailey P,
Ballard C, Barton S, Belden C, Bergthold J, Bond W, Bradley R, Braude W, Brody
M, Brown R, Burke J, Butchart J, Campbell T, Carusa S, Clarnette R, Cohen R,
Connelly P, Copeland J, Coulthard E, Crusey J, Curtis C, De Sanctis V, Demakis
G, Denburg N, Donikyan M, Doody R, Ellenbogen A, Fleischman D, Floel A,
Forchetti C, Galvez-Jimenez N, Goldstein J, Goldstein F, Goozee K, Gruener D,
Halsten J, Hassman H, Henderson E, Herbst HP, Higham S, Hofner R, Huang D,
Inglis F, Johnson C, Kass J, Kirk G, Klostermann A, Knopman A, Koplin A, Krefetz
D, Kressig R, Lai R, Lefebvre G, Leger G, Leibowitz M, Levey A, Leyhe T, Losk S,
Lyons K, Martin J, Massman P, McWilliam C, Micallef S, Middleton L, Miller H,
Mintzer J, Mitchell R, Mofsen R, Monsch A, Moore P, Munic-Miller D, Nash M,
Neugroschl J, Newson M, Noad R, Olivera E, Olley A, Omidvar O, Parra M, Pearson
S, Perneczky R, Peters O, Potter G, Price G, Raymont V, Rice L, Ritchie C,
Ritter A, Robinson J, Robinson S, Ross J, Rujescu D, Sabbagh M, Sabet A, Samson
L, Sass J, Saxena M, Schaerf F, Schlegel E, Shah R, Shingleton R, Sohrabi H,
Stephenson R, Stratmann L, Tariot P, Thein S, Till H, Voight N, Votolato R,
Wallace L, Watson D, White A, Woodward M, Zamrini E, Zimmerman C.
Author information:
(1)Zinfandel Pharmaceuticals, Durham, NC, USA. Electronic address:
[email protected].
(2)Takeda Development Center Americas, Cambridge, MA, USA.
(3)Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke
University Medical Center, Durham, NC, USA.
(4)Zinfandel Pharmaceuticals, Durham, NC, USA.
(5)Takeda Development Center Americas, Deerfield, IL, USA.
(6)Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke
University Medical Center, Durham, NC, USA; Department of Neurology, Duke
University Medical Center, Durham, NC, USA.
(7)Keck School of Medicine of the University of Southern California, Los
Angeles, CA, USA.
(8)University of California at San Francisco, San Francisco, CA, USA.
Comment in
Lancet Neurol. 2021 Jul;20(7):500-502. doi: 10.1016/S1474-4422(21)00140-X.
BACKGROUND: The identification of people at risk of cognitive impairment is
essential for improving recruitment in secondary prevention trials of
Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment
algorithm (BRAA) to identify participants at risk of developing mild cognitive
impairment due to Alzheimer's disease within 5 years, and to evaluate the safety
and efficacy of low-dose pioglitazone to delay onset of mild cognitive
impairment in these at-risk participants.
METHODS: In this phase 3, multicentre, randomised, double-blind,
placebo-controlled, parallel-group study, we enrolled cognitively healthy,
community living participants aged 65-83 years from 57 academic affiliated and
private research clinics in Australia, Germany, Switzerland, the UK, and the
USA. By use of the BRAA, participants were grouped as high risk or low risk.
Participants at high risk were randomly assigned 1:1 to receive oral
pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk
participants received placebo. Study investigators, site staff, sponsor
personnel, and study participants were masked to genotype, risk assignment, and
treatment assignment. The planned study duration was the time to accumulate 202
events of mild cognitive impairment due to Alzheimer's disease in White
participants who were at high risk (the population on whom the genetic analyses
that informed the BRAA development was done). Primary endpoints were
time-to-event comparisons between participants at high risk and low risk given
placebo (for the BRAA objective), and between participants at high risk given
pioglitazone or placebo (for the efficacy objective). The primary analysis
included all participants who were randomly assigned, received at least one dose
of study drug, and had at least one valid post-baseline visit, with significance
set at p=0·01. The safety analysis included all participants who were randomly
assigned and received at least one dose of study medication. An efficacy
futility analysis was planned for when approximately 33% of the anticipated
events occurred in the high-risk, White, non-Hispanic or Latino group. This
trial is registered with ClinicalTrials.gov, NCT01931566.
FINDINGS: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants
(3061 at high risk and 433 at low risk). Of those participants, 1545 were
randomly assigned to pioglitazone and 1516 to placebo. 1104 participants
discontinued treatment (464 assigned to the pioglitazone group, 501 in the
placebo high risk group, and 139 in the placebo low risk group). 3399
participants had at least one dose of study drug or placebo and at least one
post-baseline follow-up visit, and were included in the efficacy analysis. 3465
participants were included in the safety analysis (1531 assigned to the
pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo
low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at
high risk given placebo had mild cognitive impairment due to Alzheimer's
disease, versus four (1·0%) of 402 participants at low risk given placebo
(hazard ratio 3·26, 99% CI 0·85-12·45; p=0·023). 39 (2·7%) of 1430 participants
at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%)
of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI
0·45-1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531
participants at high risk given pioglitazone died versus 21 (1·4%) of 1507
participants at high risk given placebo. There were no other notable differences
in adverse events between groups. The study was terminated in January, 2018,
after failing to meet the non-futility threshold.
INTERPRETATION: Pioglitazone did not delay the onset of mild cognitive
impairment. The biomarker algorithm demonstrated a 3 times enrichment of events
in the high risk placebo group compared with the low risk placebo group, but did
not reach the pre-specified significance threshold. Because we did not complete
the study as planned, findings can only be considered exploratory. The conduct
of this study could prove useful to future clinical development strategies for
Alzheimer's disease prevention studies.
FUNDING: Takeda and Zinfandel.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(21)00043-0
PMID: 34146512 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests DKB, CC, SH, and AMS
are full-time employees of Zinfandel Pharmaceuticals. AMS has a patent TOMM40
Biomarker Algorithm issued, a patent Low Dose Pioglitazone in mild cognitive
impairment issued, and a patent Extended Release Formulation Low Dose
Pioglitazone issued. RCA, MC, JO, RME, PH, JW, AJS, and ER were full-time
employees of Takeda Pharmaceuticals during study conduct. KAW-B and BLP received
funding from Takeda Pharmaceuticals for their work on the project as part of the
Neuropsychology Lead Office at Duke University. Outside the submitted work,
KAW-B reports personal fees from Biogen and a grant from VeraSci. MWL received
consulting fees from Zinfandel Pharmaceuticals. JRB served as a clinical site
Principal Investigator and received funding support from Takeda Pharmaceuticals,
LSS received personal fees from Takeda Pharmaceuticals during the conduct of the
study and served as Chair of the TOMMORROW study Cognitive Impairment
Adjudication Committee. Outside of the submitted work, LSS reports grants and
personal fees from Eli Lilly, Merck, Roche/Genentech; personal fees from
Avraham, Boehringer Ingelheim, Neurim, Neuronix, Cognition, Eisai, Takeda, vTv,
Abbott, and Samus; and grants from Biogen, Novartis, Biohaven, and Washington
University/ NIA DIAN-TU. KY served as Chair of the Data Safety Monitoring Board
and reports personal fees from Alector, Eli Lilly, and the National Institutes
for Health outside the submitted work, and serves as a member of the Beeson
Scientific Advisory Board and the Global Council on Brain Health. |
http://www.ncbi.nlm.nih.gov/pubmed/28835513 | 1. Oncologist. 2017 Nov;22(11):1392-1399. doi: 10.1634/theoncologist.2017-0078.
Epub 2017 Aug 23.
FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell
Lung Cancer: First-Line Therapy and Beyond.
Pai-Scherf L(1), Blumenthal GM(2), Li H(2), Subramaniam S(2), Mishra-Kalyani
PS(2), He K(2), Zhao H(2), Yu J(2), Paciga M(2), Goldberg KB(2), McKee AE(2),
Keegan P(2), Pazdur R(2).
Author information:
(1)Center for Drug Evaluation and Research, U.S. Food and Drug Administration,
Silver Spring, Maryland, USA [email protected].
(2)Center for Drug Evaluation and Research, U.S. Food and Drug Administration,
Silver Spring, Maryland, USA.
On October 24, 2016, the U.S. Food and Drug Administration (FDA) approved
pembrolizumab (Keytruda; Merck & Co., Inc., https://www.merck.com) for treatment
of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors
express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test,
as follows: (a) first-line treatment of patients with mNSCLC whose tumors have
high PD-L1 expression (tumor proportion score [TPS] ≥50%), with no epidermal
growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor
aberrations, and (b) treatment of patients with mNSCLC whose tumors express
PD-L1 (TPS ≥1%), with disease progression on or after platinum-containing
chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have
disease progression on FDA-approved therapy for these aberrations prior to
receiving pembrolizumab.Approval was based on two randomized, open-label,
active-controlled trials demonstrating statistically significant improvements in
progression-free survival (PFS) and overall survival (OS) for patients
randomized to pembrolizumab compared with chemotherapy. In KEYNOTE-024, patients
with previously untreated mNSCLC who received pembrolizumab (200 mg
intravenously [IV] every 3 weeks) had a statistically significant improvement in
OS (hazard ratio [HR] 0.60; 95% confidence interval [CI]: 0.41-0.89; p = .005),
and significant improvement in PFS (HR 0.50; 95% CI: 0.37-0.68; p < .001). In
KEYNOTE-010, patients with disease progression on or after platinum-containing
chemotherapy received pembrolizumab IV 2 mg/kg, 10 mg/kg, or docetaxel 75 mg/m2
every 3 weeks. The HR and p value for OS was 0.71 (95% CI: 0.58-0.88), p < .001
comparing pembrolizumab 2 mg/kg with chemotherapy and the HR and p value for OS
was 0.61 (95% CI: 0.49-0.75), p < .001 comparing pembrolizumab 10 mg/kg with
chemotherapy.
IMPLICATIONS FOR PRACTICE: This is the first U.S. Food and Drug Administration
approval of a checkpoint inhibitor for first-line treatment of lung cancer. This
approval expands the pembrolizumab indication in second-line treatment of lung
cancer to include all patients with programmed death-ligand 1-expressing
non-small cell lung cancer.
Published 2017. This article is a U.S. Government work and is in the public
domain in the USA.
DOI: 10.1634/theoncologist.2017-0078
PMCID: PMC5679831
PMID: 28835513 [Indexed for MEDLINE]
Conflict of interest statement: Disclosures of potential conflicts of interest
may be found at the end of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/27995906 | 1. Am J Gastroenterol. 2017 Jan;112(1):18-35. doi: 10.1038/ajg.2016.517. Epub
2016 Dec 20.
ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries.
Kwo PY(1), Cohen SM(2), Lim JK(3).
Author information:
(1)Division of Gastroenterology/Hepatology, Department of Medicine, Stanford
University School of Medicine, Palo Alto, California, USA.
(2)Digestive Health Institute, University Hospitals Cleveland Medical Center and
Division of Gastroenterology and Liver Disease, Department of Medicine, Case
Western Reserve University School of Medicine, Cleveland, Ohio, USA.
(3)Yale Viral Hepatitis Program, Yale University School of Medicine, New Haven,
Connecticut, USA.
Clinicians are required to assess abnormal liver chemistries on a daily basis.
The most common liver chemistries ordered are serum alanine aminotransferase
(ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin.
These tests should be termed liver chemistries or liver tests. Hepatocellular
injury is defined as disproportionate elevation of AST and ALT levels compared
with alkaline phosphatase levels. Cholestatic injury is defined as
disproportionate elevation of alkaline phosphatase level as compared with AST
and ALT levels. The majority of bilirubin circulates as unconjugated bilirubin
and an elevated conjugated bilirubin implies hepatocellular disease or
cholestasis. Multiple studies have demonstrated that the presence of an elevated
ALT has been associated with increased liver-related mortality. A true healthy
normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females
and levels above this should be assessed. The degree of elevation of ALT and or
AST in the clinical setting helps guide the evaluation. The evaluation of
hepatocellular injury includes testing for viral hepatitis A, B, and C,
assessment for nonalcoholic fatty liver disease and alcoholic liver disease,
screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's
disease, and alpha-1 antitrypsin deficiency. In addition, a history of
prescribed and over-the-counter medicines should be sought. For the evaluation
of an alkaline phosphatase elevation determined to be of hepatic origin, testing
for primary biliary cholangitis and primary sclerosing cholangitis should be
undertaken. Total bilirubin elevation can occur in either cholestatic or
hepatocellular diseases. Elevated total serum bilirubin levels should be
fractionated to direct and indirect bilirubin fractions and an elevated serum
conjugated bilirubin implies hepatocellular disease or biliary obstruction in
most settings. A liver biopsy may be considered when serologic testing and
imaging fails to elucidate a diagnosis, to stage a condition, or when multiple
diagnoses are possible.
DOI: 10.1038/ajg.2016.517
PMID: 27995906 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36252444 | 1. Comput Biol Chem. 2022 Dec;101:107776. doi:
10.1016/j.compbiolchem.2022.107776. Epub 2022 Oct 10.
Computational investigations of indanedione and indanone derivatives in drug
discovery: Indanone derivatives inhibits cereblon, an E3 ubiquitin ligase
component.
Nayek U(1), Basheer Ahamed SI(2), Mansoor Hussain UH(2), Unnikrishnan MK(3),
Abdul Salam AA(4).
Author information:
(1)Department of Atomic and Molecular Physics, Manipal Academy of Higher
Education, Manipal, Karnataka 576104, India.
(2)Department of Bioinformatics, Pondicherry University, Pondicherry 605014,
India.
(3)NGSM Institute of Pharmaceutical Sciences, NITTE (Deemed to be University),
Mangaluru, Karnataka 575018, India.
(4)Department of Atomic and Molecular Physics, Manipal Academy of Higher
Education, Manipal, Karnataka 576104, India. Electronic address:
[email protected].
BACKGROUND: Cereblon, an extensively studied multifunctional protein, is a
Cullin 4-RING E3 ubiquitin ligase complex component. Cereblon is a well-known
target of thalidomide and its derivatives. Cereblon is involved in multiple
myeloma cell apoptosis. When ligands such as thalidomide and lenalidomide bind
to cereblon, it recognizes various neosubstrates based on the ligand shape and
properties. We have identified novel CRBN inhibitors, namely DHFO and its
analogs, with structural features that are slightly different from thalidomide
but stronger cereblon-binding affinity. We selected indanedione and indanone
derivatives from the literature to understand and compare their
cereblon-mediated substrate recognition potential.
METHODS: Computational investigations of possible CRBN inhibitors were
investigated by molecular docking with Autodock Vina and DockThor programs. The
properties of the compounds' ADME/T and drug-likeness were investigated. A
molecular dynamics study was carried out for four selected molecules, and the
molecular interactions were analyzed using PCA-based FEL methods. The binding
affinity was calculated using the MM/PBSA method.
RESULTS: We conducted computational investigations on 68 indanedione and
indanone derivatives binding with cereblon. Ten molecules showed better CRBN
binding affinity than thalidomide. We studied the drug-likeness properties of
the selected ten molecules, and four of the most promising molecules (DHFO,
THOH, DIMS, and DTIN) were chosen for molecular dynamics studies. The MM/PBSA
calculations showed that the DHFO, already shown to be a 5-LOX/COX2 inhibitor,
has the highest binding affinity of - 163.16 kJ/mol with cereblon.
CONCLUSION: The selected CRBN inhibitor DHFO has demonstrated the highest
binding affinity with cereblon protein compared to other molecules. Thalidomide
and its derivatives have a new substitute in the form of DHFO, which produces an
interaction hotspot on the surface of the cereblon. Ease of chemical synthesis,
low toxicity, versatile therapeutic options, and pleiotropism of DHFO analogs
provide an opportunity for exploring clinical alternatives with versatile
therapeutic potential for a new category of indanedione molecules as novel
modulators of E3 ubiquitin ligases.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.compbiolchem.2022.107776
PMID: 36252444 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Interest The authors declare no
financial or personal relationships that are received for this work from any
commercial institutions or industry. Conflict of Interest The writers affirm
that they have received no compensation from commercial organizations or
industries for this research work. |
http://www.ncbi.nlm.nih.gov/pubmed/35045330 | 1. J Mol Biol. 2022 Mar 15;434(5):167457. doi: 10.1016/j.jmb.2022.167457. Epub
2022 Jan 16.
The Ubiquitination-Dependent and -Independent Functions of Cereblon in Cancer
and Neurological Diseases.
Zhou L(1), Xu G(2).
Author information:
(1)Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of
Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational
Medicine for Geriatric Diseases, Soochow University, 199 Ren'ai Road, Suzhou,
Jiangsu 215123, China.
(2)Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of
Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational
Medicine for Geriatric Diseases, Soochow University, 199 Ren'ai Road, Suzhou,
Jiangsu 215123, China. Electronic address: [email protected].
Cereblon (CRBN) mediates the teratogenic effect of thalidomide in zebrafish,
chickens, and humans. It additionally modulates the anti-myeloma effect of the
immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide.
IMiDs bind to CRBN and recruit neo-substrates for their ubiquitination and
proteasome-mediated degradation, which significantly expands the application of
proteolysis-targeting chimeras (PROTACs) for targeted drug discovery. However,
the underlying molecular mechanisms by which CRBN mediates the teratogenicity
and anti-myeloma effect of IMiDs have not been fully elucidated. Furthermore,
the normal physiological functions of endogenous CRBN have not been extensively
studied, which prevents the thorough assessment of side effects of the CRBN
ligand-based PROTACs in the treatment of cancer and neurological diseases. To
advance our understanding of the diverse functions of CRBN, in this review, we
will survey the ubiquitination-dependent and -independent functions of CRBN,
summarize recent advances in the discovery of constitutive substrates and
neo-substrates of CRBN, and explore the molecular functions of CRBN in cancer
treatment and in the development of neurological diseases. We will also discuss
the potential future directions toward the identification of CRBN
substrates/interacting proteins and CRBN ligand-based drug discovery in the
treatment of cancer and neurological diseases.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jmb.2022.167457
PMID: 35045330 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest The authors declare that
they have no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34316334 | 1. Oncotarget. 2021 Jul 20;12(15):1555-1563. doi: 10.18632/oncotarget.27973.
eCollection 2021 Jul 20.
Developing next generation immunomodulatory drugs and their combinations in
multiple myeloma.
Thakurta A(1), Pierceall WE(1), Amatangelo MD(1), Flynt E(1), Agarwal A(2).
Author information:
(1)Translational Medicine, Bristol Myers Squibb, Summit, NJ, USA.
(2)Global Medical Affairs, Bristol Myers Squibb, Summit, NJ, USA.
Multiple Myeloma (MM) is an incurable malignancy with current treatment choices
primarily comprising combination regimens implemented with a risk-adapted
approach. Cereblon (CRBN)-targeting immunomodulatory agents (IMiDs®)
lenalidomide (LEN) and pomalidomide (POM) play a central role in combination
regimens due to their pleiotropic antitumor/immunomodulatory mechanisms that
synergize with many anti-myeloma approved or developmental agents. Currently,
more potent next generation cereblon E3 ligase modulators (CELMoDs®) -
iberdomide (IBER) and CC-92480 are in clinical development. With an expanding
number of active agents/therapeutic modalities and a myriad of combinatorial
possibilities, physicians and drug developers share an opportunity and challenge
to combine and sequence therapies to maximize long-term patient benefit.
Understanding drug mechanisms and their application in combination settings as
well as the unique disease biology considerations from newly diagnosed (NDMM),
relapsed/refractory (RRMM), and maintenance settings will be vital to guide the
development of future MM therapies centered on a backbone of IMiD or CELMoD
agents. Key aspects of drug activity are critical to consider while evaluating
potential combinations: direct antitumor effects, indirect antitumor
cytotoxicity, immune surveillance, and adverse side effects. In addition, the
treatment journey from NDMM to early and late MM relapses are connected to
genomic and immune changes associated with disease progression and acquisition
of resistance mechanisms. Based on the types of combinations used and the goals
of therapy, insights into mechanisms of drug activity and resistance may inform
treatment decisions for patients with MM. Here we focus on the evolving
understanding of the molecular mechanisms of CRBN-binding drugs and how they can
be differentiated and suggest a strategic framework to optimize efficacy and
safety of combinations using these agents.
Copyright: © 2021 Thakurta et al.
DOI: 10.18632/oncotarget.27973
PMCID: PMC8310669
PMID: 34316334
Conflict of interest statement: CONFLICTS OF INTEREST The authors report
employment and equity ownership of Bristol Myers Squibb. The opinions expressed
are those of the authors and do not represent the views of Bristol Myers Squibb. |
http://www.ncbi.nlm.nih.gov/pubmed/31202702 | 1. Pharmacol Ther. 2019 Oct;202:132-139. doi: 10.1016/j.pharmthera.2019.06.004.
Epub 2019 Jun 14.
Molecular mechanisms of cereblon-based drugs.
Asatsuma-Okumura T(1), Ito T(2), Handa H(3).
Author information:
(1)Department of Nanoparticle Translational Research, Tokyo Medical University,
Shinjuku, 160-8402, Japan.
(2)Department of Nanoparticle Translational Research, Tokyo Medical University,
Shinjuku, 160-8402, Japan; PRESTO, JST, Kawaguchi, Saitama, 332-0012, Japan.
(3)Department of Nanoparticle Translational Research, Tokyo Medical University,
Shinjuku, 160-8402, Japan. Electronic address: [email protected].
Thalidomide, well known for its potent teratogenicity, has been re-evaluated as
a clinically effective drug for the treatment of multiple myeloma. Although the
direct target of thalidomide had been unclear until recently, we identified
cereblon (CRBN) as a primary direct target of this drug by affinity purification
using ferrite glycidyl methacrylate (FG) beads in 2010. CRBN functions as a
unique substrate receptor of cullin-RING ligase 4 (CRL4). Various ligands
including thalidomide bind to CRBN and alter substrate specificity depending on
compound shape, resulting in multiple beneficial effects and/or teratogenicity.
Lenalidomide, a thalidomide derivative approved by the US Food and Drug
Administration (FDA), induces the degradation of onco-proteins such as Ikaros
and casein kinase 1 alpha (CK1α), resulting in anti-cancer effects. Recently,
novel CRBN-binding compounds have been developed and their mechanisms of action
have been analyzed, including identification of CRBN-related ubiquitin
conjugating enzymes (E2s). Moreover, the 3D structure of several
CRBN-ligand-substrate complexes has been determined. Ligands were shown to work
as a molecular glue between CRBN and its neosubstrate. In addition,
investigators have been recently developing CRBN-based proteolysis-targeting
chimeras to achieve degradation of proteins of interest. In this review, the
molecular mechanisms of classical and new CRBN-based drugs are described, and
recent advances in this field are discussed.
Copyright © 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pharmthera.2019.06.004
PMID: 31202702 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31187860 | 1. Jpn J Clin Oncol. 2019 Aug 1;49(8):695-702. doi: 10.1093/jjco/hyz083.
Immunomodulatory drugs in the treatment of multiple myeloma.
Abe Y(1), Ishida T(1).
Author information:
(1)Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.
The prognosis of multiple myeloma was quite poor in the last century, but it has
significantly improved with the incorporation of novel agents, immunomodulatory
drugs (IMiDs) and proteasome inhibitors. Thalidomide was first developed as a
sedative in 1950s, but it was withdrawn from the market because of
teratogenicity. In 1990s, however, thalidomide received attention due to the
discovery of its anticancer potential derived from antiangiogenic and
immunomodulatory activities, and its therapeutic effect on myeloma. In 2006, the
U.S. Food and Drug Administration approved the use of thalidomide under strict
control for the treatment of multiple myeloma. After that, two new IMiDs,
lenalidomide and pomalidomide, were developed for the sake of more antitumor
activity and less adverse events than thalidomide. The molecular mechanism of
action of IMiDs remained unclear for a long time until 2010 when the protein
cereblon (CRBN) was identified as a primary direct target. IMiDs binds to CRBN
and alters the substrate specificity of the CRBN E3 ubiquitin ligase complex,
resulting in breakdown of intrinsic downstream proteins such as IKZF1 (Ikaros)
and IKZF3 (Aiolos). There are many clinical trials of multiple myeloma using
IMiDs under various conditions, and most of them show the efficacy of IMiDs.
Nowadays lenalidomide plays a central role in both newly diagnosed and
relapsed/refractory settings, mainly in combination with other novel agents such
as proteasome inhibitors and monoclonal antibodies. This review presents an
overview of recent advances in immunomodulatory drugs in the treatment of
multiple myeloma.
© The Author(s) 2019. Published by Oxford University Press. All rights reserved.
For permissions, please e-mail: [email protected].
DOI: 10.1093/jjco/hyz083
PMID: 31187860 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22552008 | 1. Leukemia. 2012 Nov;26(11):2326-35. doi: 10.1038/leu.2012.119. Epub 2012 May 3.
Cereblon is a direct protein target for immunomodulatory and antiproliferative
activities of lenalidomide and pomalidomide.
Lopez-Girona A(1), Mendy D, Ito T, Miller K, Gandhi AK, Kang J, Karasawa S,
Carmel G, Jackson P, Abbasian M, Mahmoudi A, Cathers B, Rychak E, Gaidarova S,
Chen R, Schafer PH, Handa H, Daniel TO, Evans JF, Chopra R.
Author information:
(1)Celgene, San Diego, CA 92121, USA. [email protected]
Erratum in
Leukemia. 2012 Nov;26(11):2445.
Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically
active in hematological malignancies. The ubiquitously expressed E3 ligase
protein cereblon (CRBN) has been identified as the primary teratogenic target of
thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another
immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant
CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated
antiproliferative activities of lenalidomide and pomalidomide in myeloma cells,
as well as lenalidomide- and pomalidomide-induced cytokine production in T
cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in
HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not
thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type
protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified
pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in
p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929
myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R
myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was
undetectable. Our biophysical, biochemical and gene silencing studies show that
CRBN is a proximate, therapeutically important molecular target of lenalidomide
and pomalidomide.
DOI: 10.1038/leu.2012.119
PMCID: PMC3496085
PMID: 22552008 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34033753 | 1. Cell Chem Biol. 2021 Jul 15;28(7):987-999. doi:
10.1016/j.chembiol.2021.04.012. Epub 2021 May 24.
Exploiting ubiquitin ligase cereblon as a target for small-molecule compounds in
medicine and chemical biology.
Ito T(1), Yamaguchi Y(2), Handa H(3).
Author information:
(1)Department of Chemical Biology, Tokyo Medical University, 6-1-1, Shinjuku,
Shinjuku-ku 160-8402, Japan.
(2)School of Life Science and Technology, Tokyo Institute of Technology, 4259
Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
(3)Department of Chemical Biology, Tokyo Medical University, 6-1-1, Shinjuku,
Shinjuku-ku 160-8402, Japan. Electronic address: [email protected].
Cereblon (CRBN), originally identified as a gene associated with intellectual
disability, was identified as primary target of thalidomide. Accumulating
evidence has shown that CRBN is a substrate receptor of Cullin Ring E3 ubiquitin
ligase 4 (CRL4) containing DDB1, CUL4, and RBX1, which recognizes specific
neosubstrates in the presence of thalidomide or its analogs and induces their
ubiquitination and proteasomal degradation. A set of small-molecule,
CRBN-binding drugs are known as molecular glue degraders because these compounds
promote the interaction between CRBN and its neosubstrates. Moreover, CRBN-based
proteolysis-targeting chimeras, heterobifunctional molecules hijacking CRBN and
inducing degradation of proteins of interest, have emerged as a promising
modality in drug development and are being actively investigated. Meanwhile, the
original functions and regulations of CRBN are still largely elusive. In this
review, we describe key findings surrounding CRBN since its discovery and then
discuss a few unanswered issues.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.chembiol.2021.04.012
PMID: 34033753 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests H.H. received a
research support from Bristol Meyers Squibb. |
http://www.ncbi.nlm.nih.gov/pubmed/23565715 | 1. Br J Haematol. 2013 Jun;161(5):695-700. doi: 10.1111/bjh.12338. Epub 2013 Apr
9.
High expression of cereblon (CRBN) is associated with improved clinical response
in patients with multiple myeloma treated with lenalidomide and dexamethasone.
Heintel D(1), Rocci A(2), Ludwig H(1), Bolomsky A(1), Caltagirone S(2), Schreder
M(1), Pfeifer S(1), Gisslinger H(3), Zojer N(1), Jäger U(3), Palumbo A(2).
Author information:
(1)Department of Internal Medicine I, Center for Oncology and Haematology,
Wilhelminenspital, Vienna, Austria.
(2)Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S.
Giovanni Battista, Ospedale Molinette, Torino, Italy.
(3)Division of Haematology and Haemostaseology, Department of Medicine I,
Medical University of Vienna (MUW), Vienna, Austria.
Comment in
Br J Haematol. 2013 Oct;163(2):282-4. doi: 10.1111/bjh.12478.
Br J Haematol. 2013 Oct;163(2):285-6. doi: 10.1111/bjh.12477.
Cereblon (CRBN) has recently been identified as a target for immunomodulatory
drugs (IMiDs) and its downregulation has been linked to resistance to
lenalidomide. Here, we studied CRBN expression by real time polymerase chain
reaction in 49 bone marrow samples of newly diagnosed patients with multiple
myeloma treated with lenalidomide and dexamethasone. Median CRBN expression was
3·45 in patients who achieved complete response, and 3·75, 2·01, 0·78, and 0·70
in those with very good partial response, partial response, stable disease and
progressive disease respectively. CRBN expression levels correlated
significantly with response to lenalidomide treatment (r = 0·48; P < 0·001).
Among established prognostic parameters, only beta-2-microglobulin correlated
with cereblon (r = 0·66; P < 0·001). A close association of CRBN with interferon
regulatory factor 4 (IRF4) (P < 0·001) and with CTNNB1 (P < 0·001) was found.
Overall, a statistically significant association between baseline CRBN
expression and response in MM patients treated with lenalidomide is shown. CRBN
expression is closely associated with IRF4, which is an important target of IMiD
therapy.
© 2013 John Wiley & Sons Ltd.
DOI: 10.1111/bjh.12338
PMID: 23565715 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33777938 | 1. Front Cell Dev Biol. 2021 Mar 11;9:629326. doi: 10.3389/fcell.2021.629326.
eCollection 2021.
Cereblon-Based Small-Molecule Compounds to Control Neural Stem Cell
Proliferation in Regenerative Medicine.
Sato T(1)(2)(3), Ito T(1), Handa H(1).
Author information:
(1)Department of Chemical Biology, Tokyo Medical University, Tokyo, Japan.
(2)Department of Anatomy, School of Medicine, Saitama Medical University,
Saitama, Japan.
(3)Department of Obstetrics and Gynecology, School of Medicine, Saitama Medical
University, Saitama, Japan.
Thalidomide, a sedative drug that was once excluded from the market owing to its
teratogenic properties, was later found to be effective in treating multiple
myeloma. We had previously demonstrated that cereblon (CRBN) is the target of
thalidomide embryopathy and acts as a substrate receptor for the E3 ubiquitin
ligase complex, Cullin-Ring ligase 4 (CRL4CRBN) in zebrafish and chicks. CRBN
was originally identified as a gene responsible for mild intellectual disability
in humans. Fetuses exposed to thalidomide in early pregnancy were at risk of
neurodevelopmental disorders such as autism, suggesting that CRBN is involved in
prenatal brain development. Recently, we found that CRBN controls the
proliferation of neural stem cells in the developing zebrafish brain, leading to
changes in brain size. Our findings imply that CRBN is involved in neural stem
cell growth in humans. Accumulating evidence shows that CRBN is essential not
only for the teratogenic effects but also for the therapeutic effects of
thalidomide. This review summarizes recent progress in thalidomide and CRBN
research, focusing on the teratogenic and therapeutic effects. Investigation of
the molecular mechanisms underlying the therapeutic effects of thalidomide and
its derivatives, CRBN E3 ligase modulators (CELMoDs), reveals that these
modulators provide CRBN the ability to recognize neosubstrates depending on
their structure. Understanding the therapeutic effects leads to the development
of a novel technology called CRBN-based proteolysis-targeting chimeras (PROTACs)
for target protein knockdown. These studies raise the possibility that
CRBN-based small-molecule compounds regulating the proliferation of neural stem
cells may be developed for application in regenerative medicine.
Copyright © 2021 Sato, Ito and Handa.
DOI: 10.3389/fcell.2021.629326
PMCID: PMC7990905
PMID: 33777938
Conflict of interest statement: HH has received research support from
Celgene/Bristol Myers Squibb. The remaining authors declare that the research
was conducted in the absence of any commercial or financial relationships that
could be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/24328678 | 1. Br J Haematol. 2014 Mar;164(6):811-21. doi: 10.1111/bjh.12708. Epub 2013 Dec
13.
Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by
inducing degradation of T cell repressors Ikaros and Aiolos via modulation of
the E3 ubiquitin ligase complex CRL4(CRBN.).
Gandhi AK(1), Kang J, Havens CG, Conklin T, Ning Y, Wu L, Ito T, Ando H, Waldman
MF, Thakurta A, Klippel A, Handa H, Daniel TO, Schafer PH, Chopra R.
Author information:
(1)Celgene Corporation, Summit, NJ, USA.
Cereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a
substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4(CRBN) .
T cell co-stimulation by lenalidomide or pomalidomide is cereblon dependent:
however, the CRL4(CRBN) substrates responsible for T cell co-stimulation have
yet to be identified. Here we demonstrate that interaction of the transcription
factors Ikaros (IKZF1, encoded by the IKZF1 gene) and Aiolos (IKZF3, encoded by
the IKZF3 gene) with CRL4(CRBN) is induced by lenalidomide or pomalidomide. Each
agent promotes Aiolos and Ikaros binding to CRL4(CRBN) with enhanced
ubiquitination leading to cereblon-dependent proteosomal degradation in T
lymphocytes. We confirm that Aiolos and Ikaros are transcriptional repressors of
interleukin-2 expression. The findings link lenalidomide- or
pomalidomide-induced degradation of these transcriptional suppressors to well
documented T cell activation. Importantly, Aiolos could serve as a proximal
pharmacodynamic marker for lenalidomide and pomalidomide, as healthy human
subjects administered lenalidomide demonstrated Aiolos degradation in their
peripheral T cells. In conclusion, we present a molecular model in which drug
binding to cereblon results in the interaction of Ikaros and Aiolos to
CRL4(CRBN) , leading to their ubiquitination, subsequent proteasomal degradation
and T cell activation.
© 2013 The Authors. British Journal of Haematology published by John Wiley &
Sons Ltd.
DOI: 10.1111/bjh.12708
PMCID: PMC4232904
PMID: 24328678 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29530986 | 1. J Neurosci. 2018 Apr 4;38(14):3571-3583. doi: 10.1523/JNEUROSCI.2081-17.2018.
Epub 2018 Mar 12.
Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel.
Choi TY(1)(2), Lee SH(1), Kim YJ(1), Bae JR(3), Lee KM(4)(5), Jo Y(1), Kim
SJ(1), Lee AR(4), Choi S(6), Choi LM(1), Bang S(6), Song MR(4), Chung J(6), Lee
KJ(7), Kim SH(8), Park CS(9), Choi SY(10).
Author information:
(1)Department of Physiology and Dental Research Institute, Seoul National
University School of Dentistry, Seoul 03080, Republic of Korea.
(2)Department of Neural Development and Disease, Korea Brain Research Institute,
Daegu 41068, Republic of Korea.
(3)Department of Biomedical Science, Graduate School, Kyung Hee University,
Seoul 02447, Republic of Korea.
(4)School of Life Sciences, Gwangju Institute Science and Technology, Gwangju
61005, Republic of Korea.
(5)Korea Food Research Institute, Seongnam, Gyeonggi 13539, Republic of Korea.
(6)National Creative Research Initiatives Center for Energy Homeostasis
Regulation, Institute of Molecular Biology and Genetics and School of Biological
Sciences, Seoul National University, Seoul 08826, Republic of Korea.
(7)Department of Medicine, University of Ulsan College of Medicine, Asan Medical
Center, Seoul 05505, Republic of Korea, and.
(8)Department of Physiology, School of Medicine, Kyung Hee University, Seoul,
02447, Republic of Korea.
(9)School of Life Sciences, Gwangju Institute Science and Technology, Gwangju
61005, Republic of Korea, [email protected] [email protected].
(10)Department of Physiology and Dental Research Institute, Seoul National
University School of Dentistry, Seoul 03080, Republic of Korea,
[email protected] [email protected].
Comment in
J Neurosci. 2018 Sep 12;38(37):7932-7934. doi:
10.1523/JNEUROSCI.1402-18.2018.
Mutations in the cereblon (CRBN) gene cause human intellectual disability, one
of the most common cognitive disorders. However, the molecular mechanisms of
CRBN-related intellectual disability remain poorly understood. We investigated
the role of CRBN in synaptic function and animal behavior using male mouse and
Drosophila models. Crbn knock-out (KO) mice showed normal brain and spine
morphology as well as intact synaptic plasticity; however, they also exhibited
decreases in synaptic transmission and presynaptic release probability
exclusively in excitatory synapses. Presynaptic function was impaired not only
by loss of CRBN expression, but also by expression of pathogenic CRBN mutants
(human R419X mutant and Drosophila G552X mutant). We found that the BK channel
blockers paxilline and iberiotoxin reversed this decrease in presynaptic release
probability in Crbn KO mice. In addition, paxilline treatment also restored
normal cognitive behavior in Crbn KO mice. These results strongly suggest that
increased BK channel activity is the pathological mechanism of intellectual
disability in CRBN mutations.SIGNIFICANCE STATEMENTCereblon (CRBN), a well known
target of the immunomodulatory drug thalidomide, was originally identified as a
gene that causes human intellectual disability when mutated. However, the
molecular mechanisms of CRBN-related intellectual disability remain poorly
understood. Based on the idea that synaptic abnormalities are the most common
factor in cognitive dysfunction, we monitored the synaptic structure and
function of Crbn knock-out (KO) animals to identify the molecular mechanisms of
intellectual disability. Here, we found that Crbn KO animals showed cognitive
deficits caused by enhanced BK channel activity and reduced presynaptic
glutamate release. Our findings suggest a physiological pathomechanism of the
intellectual disability-related gene CRBN and will contribute to the development
of therapeutic strategies for CRBN-related intellectual disability.
Copyright © 2018 the authors 0270-6474/18/383571-13$15.00/0.
DOI: 10.1523/JNEUROSCI.2081-17.2018
PMCID: PMC6596048
PMID: 29530986 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing financial
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/26117057 | 1. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2015 Jun;23(3):892-7. doi:
10.7534/j.issn.1009-2137.2015.03.056.
[Association of CRBN Gene with Immunomodulatory Drug Resis- tance in Multiple
Myeloma].
[Article in Chinese]
Cai QQ(1), Li J(2).
Author information:
(1)Department of Hematology, Peking Union Medical College Hospital, Chinese
Academy of Medical Science & Peking Union Medical College, Beijing 100730,
China.
(2)Department of Hematology, Peking Union Medical College Hospital, Chinese
Academy of Medical Science & Peking Union Medical College, Beijing 100730,
China. E-mail: [email protected].
Human CRBN (cereblon) gene is located on chromosome 3 at 3p26 and its encoding
protein is a member of E3 ubiquitin ligase complex (composed of CRBN, DDB1,
CUL4A and ROC1). The E3 ubiquitin ligase complex functions in the
ubiquitin-proteasome protein degradation pathway and attaches polyubiquitin
chains to substrate proteins for degradation via the protease complex.
Currently, there are no standardized assays for CRBN gene and protein
measurement although quantitative reverse transcription polymerase chain
reaction (qRT-PCR), immunohistochemistry and Western blot are widely used. CRBN
has been identified as a direct target for immunomodulatory drugs (IMiD) and
plays a significant role in anti-proliferation, pro-apoptotic effects,
anti-angiogenic activities, immunomodulatory activities and intervention of cell
surface adhesion molecules between myeloma cells and bone marrow stromal cells.
Recently, clinical data show that majority of the multiple myeloma patients
treated with IMiD develop drug-resistance over time by unknown mechanisms.
Fortunately, various in vivo and in vitro studies have revealed that the
decreased CRBN expression or CRBN deletion is associated with resistance to IMiD
in treating multiple myeloma, and CRBN expression levels may have a prognostic
significance. Furthermore, the most recently discovered protein IKZF1, IKZF3,
IRF4, C/EBPβ and Wnt/catenin signaling pathways may also be closely related to
IMiD resistance in myeloma.
DOI: 10.7534/j.issn.1009-2137.2015.03.056
PMID: 26117057 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26990986 | 1. Mol Cell. 2016 Mar 17;61(6):809-20. doi: 10.1016/j.molcel.2016.02.032.
Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via
the Thalidomide Receptor Cereblon.
Nguyen TV(1), Lee JE(2), Sweredoski MJ(3), Yang SJ(4), Jeon SJ(4), Harrison
JS(5), Yim JH(6), Lee SG(7), Handa H(8), Kuhlman B(5), Jeong JS(6), Reitsma
JM(1), Park CS(4), Hess S(3), Deshaies RJ(9).
Author information:
(1)Division of Biology and Biological Engineering, California Institute of
Technology, Box 114-96, Pasadena, CA 91125, USA.
(2)Division of Biology and Biological Engineering, California Institute of
Technology, Box 114-96, Pasadena, CA 91125, USA; Center for Bioanalysis,
Division of Metrology for Quality of Life, Korea Research Institute of Standards
and Science, Daejeon 305-340, Korea.
(3)Proteome Exploration Laboratory, Division of Biology and Biological
Engineering, Beckman Institute, California Institute of Technology, Pasadena, CA
91125, USA.
(4)School of Life Sciences, National Leading Research Laboratory, and
Integrative Aging Research Center, Gwangju Institute Science and Technology
(GIST), Gwangju 500-712, Korea.
(5)Department of Biochemistry and Biophysics, University of North Carolina at
Chapel Hill, Chapel Hill, NC 27599-7260, USA.
(6)Center for Bioanalysis, Division of Metrology for Quality of Life, Korea
Research Institute of Standards and Science, Daejeon 305-340, Korea.
(7)Center for Bioanalysis, Division of Metrology for Quality of Life, Korea
Research Institute of Standards and Science, Daejeon 305-340, Korea; Department
of Biochemistry, Yonsei University, Seoul 120-749, Korea.
(8)Department of Nanoparticle Translational Research, Tokyo Medical University,
6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
(9)Division of Biology and Biological Engineering, California Institute of
Technology, Box 114-96, Pasadena, CA 91125, USA; Howard Hughes Medical
Institute. Electronic address: [email protected].
Comment in
Mol Cell. 2016 Mar 17;61(6):795-6. doi: 10.1016/j.molcel.2016.03.003.
Cereblon (CRBN), a substrate receptor for the cullin-RING ubiquitin ligase 4
(CRL4) complex, is a direct protein target for thalidomide teratogenicity and
antitumor activity of immunomodulatory drugs (IMiDs). Here we report that
glutamine synthetase (GS) is an endogenous substrate of CRL4(CRBN). Upon
exposing cells to high glutamine concentration, GS is acetylated at lysines 11
and 14, yielding a degron that is necessary and sufficient for binding and
ubiquitylation by CRL4(CRBN) and degradation by the proteasome. Binding of
acetylated degron peptides to CRBN depends on an intact thalidomide-binding
pocket but is not competitive with IMiDs. These findings reveal a feedback loop
involving CRL4(CRBN) that adjusts GS protein levels in response to glutamine and
uncover a new function for lysine acetylation.
Copyright © 2016 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2016.02.032
PMCID: PMC4889030
PMID: 26990986 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22966948 | 1. Leuk Lymphoma. 2013 Apr;54(4):683-7. doi: 10.3109/10428194.2012.728597. Epub
2012 Sep 28.
Molecular mechanism of action of immune-modulatory drugs thalidomide,
lenalidomide and pomalidomide in multiple myeloma.
Zhu YX(1), Kortuem KM, Stewart AK.
Author information:
(1)Division of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA.
Although several mechanisms have been proposed to explain the activity of
thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including
demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects,
the precise cellular targets and molecular mechanisms have only recently become
clear. A landmark study recently identified cereblon (CRBN) as a primary target
of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is
also required for the anti-myeloma activity of thalidomide and related drugs,
the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to
correlate with drug resistance in MM cell lines and primary MM cells. One of the
downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4),
which is critical for myeloma cell survival and is down-regulated by IMiD
treatment. CRBN is also implicated in several effects of IMiDs, such as
down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory
activity, demonstrating that the pleotropic actions of the IMiDs are initiated
by binding to CRBN. Future dissection of CRBN downstream signaling will help to
delineate the underlying mechanisms for IMiD action and eventually lead to
development of new drugs with more specific anti-myeloma activities. It may also
provide a biomarker to predict IMiD response and resistance.
DOI: 10.3109/10428194.2012.728597
PMCID: PMC3931443
PMID: 22966948 [Indexed for MEDLINE]
Conflict of interest statement: Potential conflict of interest: Disclosure forms
provided by the authors are available with the full text of this article at
www.informahealthcare.com/lal. |
http://www.ncbi.nlm.nih.gov/pubmed/28978850 | 1. Rinsho Ketsueki. 2017;58(10):2067-2073. doi: 10.11406/rinketsu.58.2067.
[Recent topics in IMiDs and cereblon].
[Article in Japanese]
Ito T(1)(2), Handa H(1).
Author information:
(1)Department of Nanoparticle Translational Research, Tokyo Medical University.
(2)PRESTO, JST.
Immunomodulatory drugs (IMiDs) are a new class of anticancer compounds that are
derived from thalidomide. Lenalidomide and pomalidomide are well-known IMiDs,
and they have already been approved by FDA for the treatment of several
diseases, including multiple myeloma. Cereblon (CRBN) is a common primary target
for IMiDs. It works as a substrate receptor of CRL4. Accumulating evidence has
shown that the substrate specificity of CRL4CRBN is altered by ligands such as
IMiDs. Recently, novel CRBN-binding compounds have been developed and are called
"cereblon modulators". Among these, CC-122 and CC-220 are currently under
clinical development for the treatment of diffuse large B-cell lymphoma and
systemic lupus erythematosus, respectively. Another new cereblon modulator
CC-885 is shown to induce degradation of the translation termination factor
GSPT1, resulting in an antiproliferative effect in acute myeloid leukemia.
Structural analyses have revealed that CC-885 provides an interaction hotspot
between CRBN and GSPT1. On the other hand, several groups have been
investigating linker-based approaches for targeted protein degradation via CRBN.
Several proteins, such as BRD4 and BCR-ABL, have been successfully degraded by
CRL4CRBN using these technologies. In this review, we introduce recent topics in
CRBN and its binding compounds.
DOI: 10.11406/rinketsu.58.2067
PMID: 28978850 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27294876 | 1. Nat Med. 2016 Jul;22(7):735-43. doi: 10.1038/nm.4128. Epub 2016 Jun 13.
Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor
activity and teratogenicity.
Eichner R(1), Heider M(1), Fernández-Sáiz V(1)(2)(3), van Bebber F(4), Garz
AK(1)(2)(3), Lemeer S(5), Rudelius M(6)(7), Targosz BS(1), Jacobs L(1), Knorn
AM(1), Slawska J(1), Platzbecker U(8), Germing U(9), Langer C(10), Knop S(11),
Einsele H(11), Peschel C(1)(2)(3), Haass C(4)(12)(13), Keller U(1)(2)(3), Schmid
B(4)(12), Götze KS(1)(2)(3), Kuster B(2)(3)(5)(14), Bassermann F(1)(2)(3).
Author information:
(1)Department of Medicine III, Klinikum rechts der Isar, Technische Universität
München, Munich, Germany.
(2)German Cancer Consortium (DKTK), Heidelberg, Germany.
(3)German Cancer Research Center (DKFZ), Heidelberg, Germany.
(4)German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
(5)Department of Proteomics and Bioanalytics, Technische Universität München,
Freising, Germany.
(6)Institute of Pathology, Universität Würzburg, Würzburg, Germany.
(7)Comprehensive Cancer Center Mainfranken, Universität Würzburg, Würzburg,
Germany.
(8)Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl-Gustav-Carus,
Technische Universität, Dresden, Germany.
(9)Department of Hematology, Oncology and Clinical Immunology,
Heinrich-Heine-University, Düsseldorf, Germany.
(10)Department of Internal Medicine III, University of Ulm, Ulm, Germany.
(11)Division of Hematology and Medical Oncology, Department of Internal Medicine
II, Würzburg University Medical Center, Würzburg, Germany.
(12)Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
(13)Biomedical Center, Ludwig-Maximilians University Munich, Munich, Germany.
(14)Center for Integrated Protein Science Munich (CIPSM), Freising, Germany.
Comment in
Nat Med. 2016 Jul 7;22(7):706-7. doi: 10.1038/nm.4144.
Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives
lenalidomide and pomalidomide, are key treatment modalities for hematologic
malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic
syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin
ligase complex, is the primary target by which IMiDs mediate anticancer and
teratogenic effects. Here we identify a ubiquitin-independent physiological
chaperone-like function of CRBN that promotes maturation of the basigin (BSG;
also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known
as MCT1) proteins. This process allows for the formation and activation of the
CD147-MCT1 transmembrane complex, which promotes various biological functions,
including angiogenesis, proliferation, invasion and lactate export. We found
that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to
destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells
lose CD147 and MCT1 expression after being exposed to IMiDs, whereas
IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells
have elevated CD147 expression, which is attenuated after IMiD treatment.
Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects
of thalidomide exposure in zebrafish. These findings provide a common
mechanistic framework to explain both the teratogenic and pleiotropic antitumor
effects of IMiDs.
DOI: 10.1038/nm.4128
PMID: 27294876 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33938033 | 1. J Cell Biochem. 2021 May 3. doi: 10.1002/jcb.29941. Online ahead of print.
Combined scaffold hopping, molecular screening with dynamic simulation to screen
potent CRBN ligands.
Yan J(1)(2), Sun S(2), Zhang W(2), Li P(2), Zheng Z(1)(2).
Author information:
(1)School of Chemical Engineering and Technology, Tianjin University, Tianjin,
China.
(2)Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Thalidomide and its derivatives lenalidomide and pomalidomide, known as
immunomodulatory drugs, (IMiDs) bind directly to cereblon (CRBN), a substrate
receptor of an E3 ubiquitin ligase, resulting in the rapid ubiquitination and
degradation of the substrate protein. With the discovery of the protein
degradation mechanism of IMiDs, targeted protein degradation mediated by IMiDs
via CRBN emerged and developed rapidly for the advantages of overcoming drug
resistance and targeting undruggable. To date, almost all CRBN ligands are
derived from thalidomide and there are few structural differences between them.
Hence, we employed an accurate, effective, and rational approach to screen novel
and potential CRBN ligands. In this study, we have built a molecular library by
scaffold hopping with thalidomide. ADMET screening, virtual screening, and
visual inspection screening were performed step-by-step to screen the molecular
library and five molecules were hit. Furthermore, docking analysis and a period
of 150 ns molecular dynamic (MD) simulation were performed to validate the
accuracy of our screen. The docking results showed that molecular A
(-10.42 kcal/mol), molecular B (-9.73 kcal/mol), molecular C (-9.25 kcal/mol),
molecular D (-9.09 kcal/mol), and molecular E (-10.16 kcal/mol) have lower
binding energy than thalidomide (-5.42 kcal/mol), lenalidomide (-5.74 kcal/mol),
and pomalidomide (-5.51 kcal/mol). In the MD simulation, all the five screened
molecules form key interactions with the active site amino acid residues
(Trp380, Trp386, and Trp400) as well as the three marketed IMiDs. Besides, we
found and explained that Pro352 was positive for ligand binding to CRBN and
Glu377 in reverse, which has not been reported before. We believe that our
findings and those five molecules can serve as further optimization of CRBN
ligands and development of proteolysis targeting chimeras.
© 2021 Wiley Periodicals LLC.
DOI: 10.1002/jcb.29941
PMID: 33938033 |
http://www.ncbi.nlm.nih.gov/pubmed/35780831 | 1. J Biol Chem. 2022 Aug;298(8):102227. doi: 10.1016/j.jbc.2022.102227. Epub 2022
Jul 1.
The Casein kinase 1α agonist pyrvinium attenuates Wnt-mediated CK1α degradation
via interaction with the E3 ubiquitin ligase component Cereblon.
Shen C(1), Nayak A(1), Neitzel LR(2), Yang F(1), Li B(3), Williams CH(2), Hong
CC(2), Ahmed Y(4), Lee E(5), Robbins DJ(6).
Author information:
(1)Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown
University, Washington, District of Columbia, USA; Molecular Oncology Program,
The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine,
University of Miami, Miami, Florida, USA.
(2)Department of Medicine, University of Maryland, Baltimore, Maryland, USA.
(3)Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery,
Miller School of Medicine, University of Miami, Miami, Florida, USA.
(4)Department of Molecular and Systems Biology and the Norris Cotton Cancer
Center, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire,
USA.
(5)Department of Cell and Developmental Biology, Vanderbilt University,
Nashville, Tennessee, USA.
(6)Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown
University, Washington, District of Columbia, USA. Electronic address:
[email protected].
The Cullin-RING ligase 4 E3 ubiquitin ligase component Cereblon (CRBN) is a
well-established target for a class of small molecules termed immunomodulatory
drugs (IMiDs). These drugs drive CRBN to modulate the degradation of a number of
neosubstrates required for the growth of multiple cancers. Whereas the mechanism
underlying the activation of CRBN by IMiDs is well described, the normal
physiological regulation of CRBN is poorly understood. We recently showed that
CRBN is activated following exposure to Wnt ligands and subsequently mediates
the degradation of a subset of physiological substrates. Among the Wnt-dependent
substrates of CRBN is Casein kinase 1α (CK1α), a known negative regulator of Wnt
signaling. Wnt-mediated degradation of CK1α occurs via its association with CRBN
at a known IMiD binding pocket. Herein, we demonstrate that a small-molecule
CK1α agonist, pyrvinium, directly prevents the Wnt-dependent interaction of CRBN
with CK1α, attenuating the consequent CK1α degradation. We further show that
pyrvinium disrupts the ability of CRBN to interact with CK1α at the IMiD binding
pocket within the CRBN-CK1α complex. Of note, this function of pyrvinium is
independent of its previously reported ability to enhance CK1α kinase activity.
Furthermore, we also demonstrate that pyrvinium attenuates CRBN-induced Wnt
pathway activation in vivo. Collectively, these results reveal a novel dual
mechanism through which pyrvinium inhibits Wnt signaling by both attenuating the
CRBN-mediated destabilization of CK1α and activating CK1α kinase activity.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jbc.2022.102227
PMCID: PMC9352546
PMID: 35780831 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest D. J. R. and E. L. are
founders of StemSynergy Therapeutics, Inc, a company commercializing
small-molecule signaling inhibitors, including Wnt inhibitors. All other authors
declare that they have no conflicts of interest with the contents of this
article. |
http://www.ncbi.nlm.nih.gov/pubmed/32333926 | 1. Biochim Biophys Acta Mol Cell Res. 2020 Aug;1867(8):118729. doi:
10.1016/j.bbamcr.2020.118729. Epub 2020 Apr 22.
Ubiquitin-dependent proteasomal degradation of AMPK gamma subunit by Cereblon
inhibits AMPK activity.
Yang SJ(1), Jeon SJ(1), Van Nguyen T(2), Deshaies RJ(3), Park CS(4), Lee KM(5).
Author information:
(1)School of Life Sciences and Aging Research Institute, Gwangju Institute of
Science and Technology (GIST), Gwangju 61005, Republic of Korea.
(2)Division of Biology and Biological Engineering, California Institute of
Technology, Pasadena, CA, USA.
(3)Division of Biology and Biological Engineering, and Howard Hughes Medical
Institute, California Institute of Technology, Box 114-96, Pasadena, CA 91125,
USA.
(4)School of Life Sciences and Aging Research Institute, Gwangju Institute of
Science and Technology (GIST), Gwangju 61005, Republic of Korea. Electronic
address: [email protected].
(5)Department of Life Science and Environmental Biochemistry, Pusan National
University, Miryang 50463, Republic of Korea. Electronic address:
[email protected].
Cereblon (CRBN), a substrate receptor for Cullin-ring E3 ubiquitin ligase (CRL),
is a major target protein of immunomodulatory drugs. An earlier study
demonstrated that CRBN directly interacts with the catalytic α subunit of
AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis,
down-regulating the enzymatic activity of AMPK. However, it is not clear how
CRBN modulates AMPK activity. To investigate the mechanism of CRBN-dependent
AMPK inhibition, we measured protein levels of each AMPK subunit in brains,
livers, lungs, hearts, spleens, skeletal muscles, testes, kidneys, and embryonic
fibroblasts from wild-type and Crbn-/- mice. Protein levels and stability of the
regulatory AMPKγ subunit were increased in Crbn-/- mice. Increased stability of
AMPKγ in Crbn-/- MEFs was dramatically reduced by exogenous expression of Crbn.
In wild-type MEFs, the proteasomal inhibitor MG132 blocked degradation of AMPKγ.
We also found that CRL4CRBN directly ubiquitinated AMPKγ. Taken together, these
findings suggest that CRL4CRBN regulates AMPK through ubiquitin-dependent
proteasomal degradation of AMPKγ.
Copyright © 2020 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbamcr.2020.118729
PMID: 32333926 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper. |
http://www.ncbi.nlm.nih.gov/pubmed/26002965 | 1. Blood. 2015 Aug 6;126(6):779-89. doi: 10.1182/blood-2015-02-628669. Epub 2015
May 22.
CC-122, a pleiotropic pathway modifier, mimics an interferon response and has
antitumor activity in DLBCL.
Hagner PR(1), Man HW(1), Fontanillo C(2), Wang M(3), Couto S(3), Breider M(3),
Bjorklund C(1), Havens CG(3), Lu G(3), Rychak E(3), Raymon H(3), Narla RK(3),
Barnes L(3), Khambatta G(3), Chiu H(1), Kosek J(1), Kang J(1), Amantangelo
MD(1), Waldman M(1), Lopez-Girona A(3), Cai T(1), Pourdehnad M(4), Trotter M(2),
Daniel TO(3), Schafer PH(1), Klippel A(1), Thakurta A(1), Chopra R(1), Gandhi
AK(1).
Author information:
(1)Celgene Corporation, Summit, NJ;
(2)Celgene Corporation, Sevilla, Spain;
(3)Celgene Corporation, San Diego, CA; and.
(4)Celgene Corporation, San Francisco, CA.
Comment in
Blood. 2015 Aug 6;126(6):698-700. doi: 10.1182/blood-2015-06-649483.
Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase
complex, is the target of the immunomodulatory drugs lenalidomide and
pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN
promotes the ubiquitination and subsequent degradation of 2 common substrates,
transcription factors Aiolos and Ikaros. Here we report that CC-122, a new
chemical entity termed pleiotropic pathway modifier, binds CRBN and promotes
degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T
cells in vitro, in vivo, and in patients, resulting in both cell autonomous as
well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced
degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros
correlates with increased transcription of interferon (IFN)-stimulated genes
independent of IFN-α, -β, and -γ production and/or secretion and results in
apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL cell
lines. Our results provide mechanistic insight into the cell-of-origin
independent antilymphoma activity of CC-122, in contrast to the ABC subtype
selective activity of lenalidomide.
© 2015 by The American Society of Hematology.
DOI: 10.1182/blood-2015-02-628669
PMCID: PMC4528065
PMID: 26002965 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26186254 | 1. Appl Immunohistochem Mol Morphol. 2016 Nov/Dec;24(10):695-702. doi:
10.1097/PAI.0000000000000246.
A Dual Color Immunohistochemistry Assay for Measurement of Cereblon in Multiple
Myeloma Patient Samples.
Ren Y(1), Wang M, Couto S, Hansel DE, Miller K, Lopez-Girona A, Bjorklund CC,
Gandhi AK, Thakurta A, Chopra R, Breider M.
Author information:
(1)Departments of *Exploratory Toxicology ‡Biochemistry & Structural Biology
†Celgene, San Diego, CA §Department of Translational Development, Celgene
Corporation, Summit, NJ.
Clinical interest in the measurement of Cereblon (CRBN), the primary target of
the IMiDs immunomodulatory drugs lenalidomide and pomalidomide, has been fueled
by its essential requirement for antitumor or immunomodulatory activity of both
drugs in multiple myeloma (MM). However, limited analyses of clinical samples
for CRBN gene expression or protein levels have utilized unvalidated reagents
and assays, raising uncertainty about the interpretation of these results. We
previously described a highly specific rabbit monoclonal antibody CRBN65 against
65-76 AA of human Cereblon. Here we describe a validated dual color bright-field
Cereblon/CD138 immunohistochemical (IHC) assay utilizing CRBN65 and a commercial
mouse monoclonal CD138 antibody. Sensitivity and specificity of the assay was
determined and assay precision was shown for both cytoplasmic and nuclear
Cereblon in MM bone marrow samples with coefficient of variation values of 5%
and 2%, respectively. The dual IHC assay was effective for detecting a
continuous range of Cereblon levels in 22 MM patient bone marrow core biopsies
and aspirate clots, as shown by average cytoplasmic H-scores ranging from 63 to
267 and nuclear H-scores ranging from 17 to 250. Interpathologist comparison of
MM sample H-scores by 3 pathologists demonstrated good concordance (R=0.73).
This dual assay demonstrated superior Cereblon IHC measurement in MM samples
compared with the single IHC assay using a published commercial rabbit
polyclonal Cereblon antibody and could be used to explore the potential utility
of Cereblon as a biomarker in the clinic.
DOI: 10.1097/PAI.0000000000000246
PMCID: PMC5106091
PMID: 26186254 [Indexed for MEDLINE]
Conflict of interest statement: All authors except D.E.H. are employees of
Celgene and all Celgene employees have equity ownership in Celgene Corporation.
D.E.H. is a Celgene consultant. |
http://www.ncbi.nlm.nih.gov/pubmed/33207694 | 1. Cells. 2020 Nov 16;9(11):2488. doi: 10.3390/cells9112488.
SRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion.
Conn VM(1)(2), Gabryelska M(1)(2), Marri S(1)(2), Stringer BW(1)(2)(3), Ormsby
RJ(1)(2), Penn T(1)(2), Poonnoose S(2)(4), Kichenadasse G(2)(5), Conn SJ(1)(2).
Author information:
(1)Flinders Cancer Research, College of Medicine and Public Health, Flinders
University, Bedford Park 5042, South Australia, Australia.
(2)Flinders Health and Medical Research Institute (FHMRI), College of Medicine
and Public Health, Flinders University, Bedford Park 5042, South Australia,
Australia.
(3)School of Clinical Medicine-Greenslopes Clinical Unit, The University of
Queensland, Brisbane 4120, Queensland, Australia.
(4)Department of Neurosurgery, Flinders Medical Centre, Bedford Park 5042, South
Australia, Australia.
(5)Department of Medical Oncology, Flinders Centre for Innovation in Cancer,
Flinders Medical Centre, Bedford Park 5042, South Australia, Australia.
High-throughput RNA sequencing (RNA-seq) and dedicated bioinformatics pipelines
have synergized to identify an expansive repertoire of unique circular RNAs
(circRNAs), exceeding 100,000 variants. While the vast majority of these
circRNAs comprise canonical exonic and intronic sequences, microexons
(MEs)-which occur in 30% of functional mRNA transcripts-have been entirely
overlooked. CircRNAs which contain these known MEs (ME-circRNAs) could be
identified with commonly utilized circRNA prediction pipelines, CIRCexplorer2
and CIRI2, but were not previously recognized as ME-circRNAs. In addition, when
employing a bespoke bioinformatics pipeline for identifying RNA chimeras, called
Hyb, we could also identify over 2000 ME-circRNAs which contain novel MEs at
their backsplice junctions, that are uncalled by either CIRCexplorer2 or CIRI2.
Analysis of circRNA-seq datasets from gliomas of varying clinical grades
compared with matched control tissue has shown circRNAs have potential as
prognostic markers for stratifying tumor from healthy tissue. Furthermore, the
abundance of microexon-containing circRNAs (ME-circRNAs) between tumor and
normal tissues is correlated with the expression of a splicing associated
factor, Serine/arginine repetitive matrix 4 (SRRM4). Overexpressing SRRM4, known
for regulating ME inclusion in mRNAs critical for neural differentiation, in
human HEK293 cells resulted in the biogenesis of over 2000 novel ME-circRNAs,
including ME-circEIF4G3, and changes in the abundance of many canonical
circRNAs, including circSETDB2 and circLBRA. This shows SRRM4, in which its
expression is correlated with poor prognosis in gliomas, acts as a bona fide
circRNA biogenesis factor. Given the known roles of MEs and circRNAs in
oncogenesis, the identification of these previously unrecognized ME-circRNAs
further increases the complexity and functional purview of this non-coding RNA
family.
DOI: 10.3390/cells9112488
PMCID: PMC7697094
PMID: 33207694 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/25626321 | 1. Nihon Rinsho. 2015 Jan;73(1):149-55.
[Thalidomide, cereblon and multiple myeloma].
[Article in Japanese]
Ogura T.
Cereblon was identified as a direct target of thalidomide by Prof. H. Handa, and
this pioneering work triggered active research on IMiDs (immunomodulatory
drugs), which include thalidomide-derivatives, such as lenalidomide and
pomalidomide. These small molecules have been shown to bind to cereblon (CRBN)
to modulate its activity as a substrate receptor. In addition, structural
analyses on CRBN have revealed unique actions of these small agents, by which
degradation of transcription factors is controlled in a specific and unique way.
I summarize recent progress on CRBN-CRLA ubiquitin ligase and IMiDs, focusing on
the therapeutic application of these drugs for treatment of multiple myeloma.
PMID: 25626321 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35914259 | 1. Ann Intern Med. 2022 Aug;175(8):JC92. doi: 10.7326/J22-0056. Epub 2022 Aug 2.
In persons at risk for poor vaccination response or COVID-19 exposure,
tixagevimab + cilgavimab reduced COVID-19.
Aisenberg GM(1).
Author information:
(1)University of Texas, Houston, Houston, Texas, USA (G.M.A.).
Comment on
N Engl J Med. 2022 Jun 9;386(23):2188-2200. doi: 10.1056/NEJMoa2116620.
Levin MJ, Ustianowski A, De Wit S, et al. Intramuscular AZD7442
(tixagevimab-cilgavimab) for prevention of Covid-19. N Engl J Med.
2022;386:2188-200. 35443106.
DOI: 10.7326/J22-0056
PMID: 35914259 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35993765 | 1. Microbiol Spectr. 2022 Oct 26;10(5):e0103422. doi: 10.1128/spectrum.01034-22.
Epub 2022 Aug 22.
Qualification of a Biolayer Interferometry Assay to Support AZD7442 Resistance
Monitoring.
Brady T(#)(1), Zhang T(#)(2), Tuffy KM(1), Haskins N(3), Du Q(3), Lin J(3),
Kaplan G(3), Novick S(2), Roe TL(1), Ren K(4), Rosenthal K(4), McTamney PM(4),
Abram ME(1), Streicher K(1), Kelly EJ(1).
Author information:
(1)Translational Medicine, Vaccines and Immune Therapies, BioPharmaceuticals
R&D, AstraZeneca, Gaithersburg, Maryland, USA.
(2)Data Sciences and Quantitative Biology, AstraZeneca, Gaithersburg, Maryland,
USA.
(3)Biologics Engineering, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
(4)Virology and Vaccine Discovery, Vaccines and Immune Therapies,
BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA.
(#)Contributed equally
AZD7442, a combination of two long-acting monoclonal antibodies (tixagevimab
[AZD8895] and cilgavimab [AZD1061]), has been authorized for the prevention and
treatment of coronavirus disease 2019 (COVID-19). The rapid emergence of severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants requires methods
capable of quickly characterizing resistance to AZD7442. To support AZD7442
resistance monitoring, a biolayer interferometry (BLI) assay was developed to
screen the binding of tixagevimab and cilgavimab to SARS-CoV-2 spike proteins to
reduce the number of viral variants for neutralization susceptibility
verification. Six spike variants were chosen to assess the assay's performance:
four with decreased affinity for tixagevimab (F486S:D614G and F486W:D614G
proteins) or cilgavimab (S494L:D614G and K444R:D614G proteins) and two reference
proteins (wild-type HexaPro and D614G protein). Equilibrium dissociation
constant (KD) values from each spike protein were used to determine shifts in
binding affinity. The assay's precision, range, linearity, and limits of
quantitation were established. Qualification acceptance criteria determined
whether the assay was fit for purpose. By bypassing protein purification, the
BLI assay provided increased screening throughput. Although limited correlation
between pseudotype neutralization and BLI data (50% inhibitory concentration
versus KD) was observed for full immunoglobulins (IgGs), the correlations for
antibody fragments (Fabs) were stronger and reflected a better comparison of
antibody binding kinetics with neutralization potency. Therefore, despite strong
assay performance characteristics, the use of full IgGs limited the screening
utility of the assay; however, the Fab approach warrants further exploration as
a rapid, high-throughput variant-screening method for future
resistance-monitoring programs. IMPORTANCE SARS-CoV-2 variants harbor multiple
substitutions in their spike trimers, potentially leading to breakthrough
infections and clinical resistance to immune therapies. For this reason, a BLI
assay was developed and qualified to evaluate the reliability of screening
SARS-CoV-2 spike trimer variants against anti-SARS-CoV-2 monoclonal antibodies
(MAbs) tixagevimab and cilgavimab, the components of AZD7442, prior to in vitro
pseudovirus neutralization susceptibility verification testing. The assay
bypasses protein purification with rapid assessment of the binding affinity of
each MAb for each recombinant protein, potentially providing an efficient
preliminary selection step, thus allowing a reduced testing burden in the more
technically complex viral neutralization assays. Despite precise and specific
measures, an avidity effect associated with MAb binding to the trimer confounded
correlation with neutralization potency, negating the assay's utility as a
surrogate for neutralizing antibody potency. Improved correlation with Fabs
suggests that assay optimization could overcome any avidity limitation,
warranting further exploration to support future resistance-monitoring programs.
DOI: 10.1128/spectrum.01034-22
PMCID: PMC9704045
PMID: 35993765 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare a conflict of interest. All
authors are employees of AstraZeneca and hold, or may hold, AstraZeneca stock
options. |
http://www.ncbi.nlm.nih.gov/pubmed/35904210 | 1. Clin Infect Dis. 2023 Feb 8;76(3):e126-e132. doi: 10.1093/cid/ciac625.
Association Between AZD7442 (Tixagevimab-Cilgavimab) Administration and Severe
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection,
Hospitalization, and Mortality.
Kertes J(1), Shapiro Ben David S(2)(3), Engel-Zohar N(4), Rosen K(1)(3), Hemo
B(1), Kantor A(1), Adler L(1)(3), Shamir Stein N(1), Mizrahi Reuveni M(2),
Shahar A(4).
Author information:
(1)Department of Health Evaluation and Research, Maccabi HealthCare Services,
Tel Aviv-Jaffa, Israel.
(2)Division of Health, Maccabi HealthCare Services, Tel Aviv-Jaffa, Israel.
(3)Sackler Faculty of Medicine, Department of Family Medicine, Tel Aviv
University, Tel Aviv, Israel.
(4)Division of Data and Digital Health, Maccabi HealthCare Services, Tel
Aviv-Jaffa, Israel.
BACKGROUND: Intramuscular AZD7442 (tixagevimab-cilgavimab [Evusheld;
AstraZeneca]) has been found effective among immunocompromised individuals
(ICIs) in reducing SARS-CoV-2 infection and severe disease in ICIs. We evaluated
the association between AZD7442 administration and SARS-CoV-2 infection and
severe disease (COVID-19 hospitalization and all-cause mortality) among selected
ICIs, during a fifth Omicron-dominated wave of COVID-19 (December 2021-April
2022) in Israel.
METHODS: ICIs aged ≥12 years identified in the Maccabi HealthCare Services
database were invited by SMS/e-mail to receive AZD7442. Demographic information,
comorbidities, coronavirus vaccination, and prior SARS-CoV-2 infection and
COVID-19 outcome data (infection, severe disease) were extracted from the
database. Rates of infection and severe disease were compared between those
administered AZD7442 and those who did not respond to the invitation over a
3-month period.
RESULTS: Of all 825 ICIs administered AZD7442, 29 (3.5%) became infected with
SARS-CoV-2 compared with 308 (7.2%) of 4299 ICIs not administered AZD7442 (P <
.001). After adjustment, the AZD7442 group was half as likely to become infected
with SARS-CoV-2 than the nonadministered group (OR: .51; 95% CI: .30-.84). One
person in the AZD7442 group (0.1%) was hospitalized for COVID-19 compared with
27 (0.6%) in the nonadministered group (P = .07). No mortality was recorded
among the AZD7442 group compared with 40 deaths (0.9%) in the nonadministered
group (P = .005). After adjustment, ICIs administered AZD7442 were 92% less
likely to be hospitalized/die than those not administered AZD7442 (OR: .08; 95%
CI: .01-.54).
CONCLUSIONS: AZD7442 among ICIs may protect against Omicron variant infection
and severe disease and should be considered for pre-exposure prophylactic
AZD7442.
© The Author(s) 2022. Published by Oxford University Press on behalf of
Infectious Diseases Society of America. All rights reserved. For permissions,
please e-mail: [email protected].
DOI: 10.1093/cid/ciac625
PMCID: PMC9384583
PMID: 35904210 [Indexed for MEDLINE]
Conflict of interest statement: Potential conflicts of interest. S. S. B. D. and
L. A. have both received funding for research from Pfizer. None of the authors
have received funding for any purpose from AstraZeneca (maker/supplier of
AZD7442). S. S. B. D. reports receiving payment from Pfizer for a lecture. L. A.
reports payments made to their institution from Pfizer (grant number 65254759)
for a study about varenicline. All other authors report no potential conflicts.
All authors are employed by Maccabi HealthCare Services. The study was carried
out in the interests of Maccabi members. All authors have submitted the ICMJE
Form for Disclosure of Potential Conflicts of Interest. Conflicts that the
editors consider relevant to the content of the manuscript have been disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/26822752 | 1. Pharmacotherapy. 2016 Mar;36(3):317-34. doi: 10.1002/phar.1714.
PD-1 Pathway Inhibitors: Immuno-Oncology Agents for Restoring Antitumor Immune
Responses.
Medina PJ(1), Adams VR(2).
Author information:
(1)Department of Pharmacy: Clinical and Administrative Sciences, The University
of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma.
(2)Pharmacy Practice and Science Department, University of Kentucky College of
Pharmacy, Lexington, Kentucky.
Immune checkpoint inhibitors are designed to restore a patient's own antitumor
immune response that has been suppressed during tumor development. The first
monoclonal antibodies against the immune checkpoint programmed death 1 (PD-1)
receptor, nivolumab and pembrolizumab, are now approved for clinical use. Both
agents are indicated for the treatment of advanced melanoma, as well as for the
treatment of metastatic non-small cell lung cancer (NSCLC). Nivolumab is also
approved for the treatment of advanced renal cell carcinoma. In patients with
melanoma, these agents result in objective response rates of ~25-40%, with
durable responses lasting more than 2 years in some cases. Results from phase
III trials have shown improved survival with nivolumab versus standard-of-care
chemotherapy in both patients with advanced melanoma and those with advanced
NSCLC. In patients with advanced melanoma, both PD-1 inhibitors (nivolumab and
pembrolizumab) have shown improved survival versus ipilimumab. PD-1 inhibitors
are associated with adverse events that have immune etiologies, with grade
greater than 3 adverse events typically reported in 16% or less of patients.
However, most immune-mediated adverse events (including grade 3-4 adverse
events) can be managed by using published management algorithms without
permanent discontinuation of the agent. As nivolumab and pembrolizumab enter the
clinic, and with more PD-1 pathway agents in development for a range of tumor
types, this review aims to provide pharmacists with a basic understanding of the
role of PD-1 in modulating the immune system and their use in the cancer
treatment. The most recent clinical efficacy and safety data are discussed,
highlighting the response characteristics distinctive to immune checkpoint
inhibitors, along with pharmacokinetic and pharmacodynamic data and cost
considerations.
© 2016 The Authors. Pharmacotherapy published by Wiley Periodicals, Inc. on
behalf of Pharmacotherapy Publications, Inc.
DOI: 10.1002/phar.1714
PMCID: PMC5071694
PMID: 26822752 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32984529 | 1. AACE Clin Case Rep. 2020 Sep 21;6(5):e239-e242. doi: 10.4158/ACCR-2020-0100.
eCollection 2020 Sep-Oct.
CAUTION ADVISED USING COMBINATION KETOCONAZOLE AND PD-1 INHIBITORS.
Yang Y(1), Hecht JR(2), Liu ST(1), Cohen MJ(1), Hart SD(3), Wang HL(3), Heaney
AP(1).
Author information:
(1)Divisions of Endocrinology, David Geffen School of Medicine at UCLA,
University of California, Los Angeles, California.
(2)Hematology and Oncology, David Geffen School of Medicine at UCLA, University
of California, Los Angeles, California.
(3)Department of Pathology and Laboratory Medicine, David Geffen School of
Medicine at UCLA, University of California, Los Angeles, California.
OBJECTIVE: Immune checkpoint inhibitors are approved to treat multiple cancers.
We report life-threatening hepatic failure in 2 consecutive patients with
Cushing syndrome that were treated with ketoconazole (KTZ) in combination with 2
different programmed cell death protein 1 (PD-1) inhibitors, Nivolumab and
Pembrolizumab.
METHODS: The first patient suffered from corticotroph pituitary carcinoma and
the second from metastatic adrenal cortical carcinoma. They were both treated
with KTZ for tumor-associated hypercortisolism.
RESULTS: Hepatic function was normal on KTZ prior to initiation of PD-1
inhibitors, after which they rapidly developed severe hepatic dysfunction. In
both cases, liver biopsy was consistent with drug-induced hepatic injury. Liver
function fully recovered on discontinuing KTZ and the PD-1 inhibitors along with
methylprednisone therapy.
CONCLUSION: Antifungal azole therapy is commonly used in oncology patients who
may be co-treated with PD-1 inhibitors. Although the specific combination of KTZ
and PD-1 inhibitors to treat Cushing syndrome may be relatively uncommon, we
recommend careful monitoring of hepatic function using a combination PD-1
inhibitors and azole antifungal agents, especially KTZ, due to the potential of
life-threatening hepatic failure.
Copyright © 2020 AACE.
DOI: 10.4158/ACCR-2020-0100
PMCID: PMC7511096
PMID: 32984529
Conflict of interest statement: DISCLOSURE The authors have no multiplicity of
interest to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/25682878 | 1. Oncotarget. 2015 Feb 28;6(6):3479-92. doi: 10.18632/oncotarget.2980.
PD-1 pathway inhibitors: the next generation of immunotherapy for advanced
melanoma.
Luke JJ(1), Ott PA(2).
Author information:
(1)Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
(2)Melanoma Disease Center, Dana Farber Cancer Institute and Harvard Medical
School, Boston, MA, USA.
Checkpoint inhibitors are revolutionizing treatment options and expectations for
patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic
T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint
inhibitor. Emerging long-term data indicate that approximately 20% of
ipilimumab-treated patients achieve long-term survival. The first programmed
death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United
States Food and Drug Administration for the treatment of melanoma; nivolumab was
previously approved in Japan. PD-1 inhibitors are also poised to become standard
of care treatment for other cancers, including non-small cell lung cancer, renal
cell carcinoma and Hodgkin's lymphoma. Immunotherapy using checkpoint inhibition
is a different treatment approach to chemotherapy and targeted agents: instead
of directly acting on the tumor to induce tumor cell death, checkpoint
inhibitors enhance or de novo stimulate antitumor immune responses to eliminate
cancer cells. Initial data suggest that objective anti-tumor response rates may
be higher with anti-PD-1 agents compared with ipilimumab and the safety profile
may be more tolerable. This review explores the development and next steps for
PD-1 pathway inhibitors, including discussion of their novel mechanism of action
and clinical data to-date, with a focus on melanoma.
DOI: 10.18632/oncotarget.2980
PMCID: PMC4414130
PMID: 25682878 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest statement Dr. Luke reports
consultancy and travel from Amgen, Bayer, and Genentech, and clinical trial
support to his institution from EMD Serono, GlaxoSmithKline, and Novartis. Dr.
Ott reports consultancy from Bristol-Myers Squibb and clinical trial support to
his institution from ARMO BioSciences, Bristol-Myers Squibb, MedImmune, and
Merck. |
http://www.ncbi.nlm.nih.gov/pubmed/29357948 | 1. J Immunother Cancer. 2018 Jan 23;6(1):8. doi: 10.1186/s40425-018-0316-z.
Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a
comprehensive review of registration trials and future considerations.
Gong J(1), Chehrazi-Raffle A(2), Reddi S(2), Salgia R(3).
Author information:
(1)Department of Medical Oncology, City of Hope National Medical Center, 1500 E
Duarte St, Duarte, CA, 91010, USA.
(2)Department of Internal Medicine, Harbor-UCLA Medical Center, 1000 W Carson
St, Torrance, CA, 90509, USA.
(3)Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive
Cancer Center, Building 51, Room 101, 1500 E Duarte St, Duarte, CA, 91010, USA.
[email protected].
Early preclinical evidence provided the rationale for programmed cell death 1
(PD-1) and programmed death ligand 1 (PD-L1) blockade as a potential form of
cancer immunotherapy given that activation of the PD-1/PD-L1 axis putatively
served as a mechanism for tumor evasion of host tumor antigen-specific T-cell
immunity. Early-phase studies investigating several humanized monoclonal IgG4
antibodies targeting PD-1 and PD-L1 in advanced solid tumors paved way for the
development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved
by the Food and Drug Administration (FDA) in 2014. The number of FDA-approved
agents of this class is rapidly enlarging with indications for treatment
spanning across a spectrum of malignancies. The purpose of this review is to
highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer
therapy to date. In particular, we focus on detailing the registration trials
that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies
in cancer. As the number of PD-1/PD-L1 inhibitors continues to grow, predictive
biomarkers, mechanisms of resistance, hyperprogressors, treatment duration and
treatment beyond progression, immune-related toxicities, and clinical trial
design are key concepts in need of further consideration to optimize the
anticancer potential of this class of immunotherapy.
DOI: 10.1186/s40425-018-0316-z
PMCID: PMC5778665
PMID: 29357948 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable CONSENT FOR PUBLICATION: Not applicable COMPETING INTERESTS: The
authors declare that they have no competing interests. PUBLISHER’S NOTE:
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/29222273 | 1. Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):317-323. doi:
10.1182/asheducation-2017.1.317.
Emerging role of novel therapies in Hodgkin lymphoma: proceed with caution.
Bartlett NL(1).
Author information:
(1)Washington University School of Medicine, Siteman Cancer Center, St. Louis,
MO.
Based on very high response rates in the relapsed and refractory setting,
brentuximab vedotin and the programmed cell death protein 1 (PD-1) inhibitors,
nivolumab and pembrolizumab, have quickly been incorporated into clinical trials
for first- and second-line therapy of Hodgkin lymphoma. Preliminary data show
that brentuximab vedotin alone is not adequate therapy for newly diagnosed
Hodgkin lymphoma in older patients, but modestly decreases the risk of relapse
when combined with adriamycin, vinblastine, and dacarbazine in patients with
previously untreated advanced-stage disease. In second-line therapy, combining
brentuximab vedotin with conventional chemotherapy or with PD-1 inhibitors as
pretransplant salvage is associated with high overall and complete response
rates, although further follow up is needed to assess whether posttransplant
outcomes are improved. Although these new drugs are well tolerated when given as
single agents, unexpected toxicities have been encountered with combination
regimens, specifically severe pulmonary toxicity with the bleomycin and
brentuximab vedotin combination and frequent infusion-related reactions. There
is concern with the use of PD-1 inhibitors as first-line therapy due to the
theoretical potential for more frequent or severe immune-mediated toxicities in
patients who have not received prior chemotherapy. Aside from these concerns,
these new agents have the potential to improve outcomes for patients even
further, bringing us closer to eradicating recurrent Hodgkin lymphoma.
© 2016 by The American Society of Hematology. All rights reserved.
DOI: 10.1182/asheducation-2017.1.317
PMCID: PMC6142541
PMID: 29222273 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest disclosure: N.L.B. is on
the Board of Directors or an advisory committee and has consulted for Pfizer,
KITE, Gilead, and Seattle Genetics, and has received research funding from
Pfizer, KITE, Merck & Co, Bristol-Myers Squibb, Immune Design, Forty Seven,
Affimed, Janssen, Pharmacyclics, Millennium, Astra Zeneca, ImaginAB, Novartis,
Genentech, Seattle Genetics, and Celgene. |