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ID: ALA5223124
Journal: RSC Med Chem
Title: Recent applications of covalent chemistries in protein-protein interaction inhibitors.
Authors: Chan AM, Goodis CC, Pommier EG, Fletcher S.
Abstract: Protein-protein interactions (PPIs) are large, often featureless domains whose modulations by small-molecules are challenging. Whilst there are some notable successes, such as the BCL-2 inhibitor venetoclax, the requirement for larger ligands to achieve the desired level of potency and selectivity may result in poor "drug-like" properties. Covalent chemistry is presently enjoying a renaissance. In particular, targeted covalent inhibition (TCI), in which a weakly electrophilic "warhead" is installed onto a protein ligand scaffold, is a powerful strategy to develop potent inhibitors of PPIs that are smaller/more drug-like yet have enhanced affinities by virtue of the reinforcing effect on the existing non-covalent interactions by the resulting protein-ligand covalent bond. Furthermore, the covalent bond delivers sustained inhibition, which may translate into significantly reduced therapeutic dosing. Herein, we discuss recent applications of a spectrum of TCIs, as well as covalent screening strategies, in the discovery of more effective inhibitors of PPIs using the HDM2 and BCL-2 protein families as case studies.
CiteXplore: 36092144
DOI: 10.1039/d2md00112h