Journal ArticleDOI
Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies.
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TLDR
Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious disease.About:
This article is published in Drug Discovery Today.The article was published on 2015-09-01. It has received 385 citations till now. The article focuses on the topics: Drug.read more
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Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity.
Hongbin He,Hua Jiang,Yun Chen,Jin Ye,Aoli Wang,Chao Wang,Qingsong Liu,Gaolin Liang,Xianming Deng,Wei Jiang,Rongbin Zhou +10 more
TL;DR: Ori can be covalently linked to NLRP3 to prevent assembly of theNLRP3 inflammasome, and to ameliorate inflammation in several mouse disease models, and could serve as a lead for developing new therapeutics against NL RP3-driven diseases.
Journal ArticleDOI
Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology
Matthias Gehringer,Stefan Laufer +1 more
TL;DR: An overview of warheads-beyond α,β-unsaturated amides-recently used in the design of targeted covalent ligands is provided, with special emphasis on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.
Journal ArticleDOI
Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions
TL;DR: This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors.
Journal ArticleDOI
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.
Alice Douangamath,D. Fearon,P. Gehrtz,T. Krojer,Petra Lukacik,C. David Owen,Efrat Resnick,Claire Strain-Damerell,A. Aimon,Péter Ábrányi-Balogh,José Brandão-Neto,Anna Carbery,Gemma Davison,Alexandre Dias,Thomas D. Downes,Louise Dunnett,Michael Fairhead,James D. Firth,S. Paul Jones,Aaron Keeley,G.M. Keseru,Hanna F. Klein,Mathew P. Martin,Martin E.M. Noble,Peter O'Brien,A.J. Powell,Rambabu N. Reddi,R. Skyner,M. Snee,Michael J. Waring,Conor Wild,Nir London,Frank von Delft,Martin A. Walsh +33 more
TL;DR: A large-scale screen of electrophile and non-covalent fragments is performed through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication.
Journal ArticleDOI
Redox Signaling by Reactive Electrophiles and Oxidants
TL;DR: This Review reflects on five aspects critical for understanding how nature harnesses these noncanonical post-translational modifications to coordinate distinct cellular activities: specific players and their generation, physicochemical properties, mechanisms of action, methods of interrogation, and functional roles in health and disease.
References
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Journal ArticleDOI
Can the pharmaceutical industry reduce attrition rates
Ismail Kola,John Landis +1 more
TL;DR: The pharmaceutical industry faces considerable challenges, both politically and fiscally, and the fiscal pressures that face the industry from the perspective of R&D are dealt with.
Journal ArticleDOI
A systematic review of the associations between dose regimens and medication compliance
TL;DR: A review of studies that measured compliance using EM confirmed that the prescribed number of doses per day is inversely related to compliance.
Journal ArticleDOI
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Cai-Hong Yun,Kristen E. Mengwasser,Angela V. Toms,Michele S. Woo,Heidi Greulich,Heidi Greulich,Kwok-Kin Wong,Kwok-Kin Wong,Matthew Meyerson,Matthew Meyerson,Michael J. Eck +10 more
TL;DR: It is concluded that the T790M mutation is a “generic” resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.
Journal ArticleDOI
Acetaminophen-induced hepatic necrosis. VI. Metabolic disposition of toxic and nontoxic doses of acetaminophen.
TL;DR: The relationship between the metabolic disposition of acetaminophen and the susceptibility of hamsters, mice and rats toacetaminophen-induced liver necrosis has been examined.
Journal ArticleDOI
The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy
Lee Honigberg,Ashley M. Smith,Mint Sirisawad,Erik Verner,David Loury,Betty Y. Chang,Shyr Li,Zhengying Pan,Douglas H. Thamm,Richard A. Miller,Joseph J. Buggy +10 more
TL;DR: Findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.