Abstract
Abstract Cysteine-focused chemical proteomic platforms have expanded the repertoire of protein targets for covalent inhibitors. However, it remains unknown how cysteine targeting varies across multiple cancer contexts. To address this question, we compiled an atlas of cysteine ligandability across 417 cancer cell lines. We unexpectedly find that cysteine ligandability fluctuates across cancers, which we attribute to differences in cellular redox state, protein complex formation and mutation. Focusing on lineage-restricted liganding, we identify highly actionable cysteines in SOX10, leveraging this information to develop covalent inhibitors. We find the SOX10 ligand functions as a covalent molecular glue and disrupts transcriptional activity in a dominant negative manner. Our findings reveal pervasive heterogeneity in cysteine ligandability across cancer, pinpoint cell-intrinsic features driving cysteine targeting, and exemplify the use of covalent probes to disrupt [BPL2] oncogenic transcription factor activity. Citation Format: Liron Bar-Peled. DrugMap: A quantitative pan-cancer analysis of cysteine ligandability [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B22.
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