Issue 8, 2022

Recent applications of covalent chemistries in protein–protein interaction inhibitors

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.

Graphical abstract: Recent applications of covalent chemistries in protein–protein interaction inhibitors

Article information

Article type
Review Article
Submitted
08 Кві 2022
Accepted
30 Тра 2022
First published
03 Чер 2022

RSC Med. Chem., 2022,13, 921-928

Recent applications of covalent chemistries in protein–protein interaction inhibitors

A. M. Chan, C. C. Goodis, E. G. Pommier and S. Fletcher, RSC Med. Chem., 2022, 13, 921 DOI: 10.1039/D2MD00112H

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