Proteome-wide ligandability maps of drugs with diverse cysteine-reactive chemotypes.

ABSTRACT: Covalent drug discovery has experienced a revival since the 2013 approval of the first cysteine-targeting kinase inhibitors. Many drugs that were discovered by serendipity also possess the ability to react with cysteine residues, leading to interactions with multiple proteins. This widespread interaction, known as promiscuity, necessitates a comprehensive study of how these drugs engage with cysteines throughout the proteome. Here we report a large-scale analysis to meet this need by defining proteome-wide cysteine ligandability maps of 70 drugs in native biological systems. We examined over 24,000 cysteines in the human proteome, pinpointing 279 proteins as potential drug targets across diverse functional categories. We further validated several cysteine engagement events, uncovering prev

SUBMITTER: Tian C 

PROVIDER: S-EPMC12106687 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature