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Approaches to mitigate the risk of serious adverse reactions in covalent drug design
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TLDR
High selectivity for the intended protein target has emerged as a key consideration in mitigating safety risks associated with widespread proteome reactivity, and Optimizing pharmacokinetics to capitalize on the intrinsically high potency of covalent drugs should lead to low daily doses and greater safety margins, while minimizing susceptibility to metabolic activation likewise will attenuate the risk ofcovalent drug toxicity.Abstract:
Covalent inhibition of target proteins using high affinity ligands bearing weakly electrophilic warheads is being adopted increasingly as design strategy in the discovery of novel therapeutics, and...read more
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Orally effective FDA-approved protein kinase targeted covalent inhibitors (TCIs)
TL;DR: Covalent inhibitors have emerged from the ranks of drugs to be avoided to become an emerging paradigm in the development of enzyme antagonists and receptor modulators as mentioned in this paper and have become one of the most important drug targets of the 21st century.
Journal ArticleDOI
Boronic acid with high oxidative stability and utility in biological contexts.
TL;DR: In this paper, a carboxyl group was used as an intramolecular ligand for the boron to increase the stability of the p orbital of the boralactone.
Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology
Natalia Sacilotto,Paola Dessanti,Michele Matteo Pio Lufino,Alberto Ortega,Alejandra Rodríguez-Gimeno,Jordi Salas,Tamara Maes,Carlos Buesa,Cristina Mascaró,Robert Soliva +9 more
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Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK.
Michael Forster,Xiaojun Julia Liang,Martin Schröder,Martin Schröder,Stefan Gerstenecker,Apirat Chaikuad,Apirat Chaikuad,Stefan Knapp,Stefan Knapp,Stefan Laufer,Matthias Gehringer +10 more
TL;DR: A novel class of dual BMX/BTK inhibitors were designed from irreversible inhibitors of Janus kinase (JAK) 3 targeting a cysteine located within the solvent-exposed front region of the ATP binding pocket, enabling the achievement of high selectivity over JAK3 and certain other kinases harboring a sterically demanding residue at this position.
Journal ArticleDOI
Mercapturate pathway metabolites of sotorasib, a covalent inhibitor of KRASG12C, are associated with renal toxicity in the Sprague Dawley rat.
Jonathan Werner,Rhian Davies,Jan Wahlstrom,Upendra P. Dahal,Min Jiang,Jonathan Stauber,Benjamin David,William Siska,Barbara Thomas,Katsu Ishida,W. Griffith Humphreys,J. Russell Lipford,Thomas M. Monticello +12 more
TL;DR: In this paper, an in vivo mechanistic rat study designed to investigate the time course of the renal toxicity and sotorasib metabolites was performed, and the morphologic features progressed from vacuolation and necrosis to regeneration of tubular epithelium.
References
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Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
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