Several important medicines produce a therapeutic response through a covalent mechanism of action. The renewed interest in covalent inhibitors is driven by the potential for high ligand efficiency and potency, prolonged duration of action, and access to unreachable protein targets. I will describe the synthesis of sulfonyl-triazoles as a new phenol-reactive group for selective modification of tyrosine residues on proteins through sulfur-triazole exchange (SuTEx) chemistry. Our initial studies demonstrated that sulfonyl-triazoles can serve as global detection probes and fragment competitors for surveying ligandability of protein sites. We further showcase the high tunability of sulfonyl-triazoles for developing inhibitors that can disrupt protein function by liganding catalytic and non-catalytic tyrosine sites. I will conclude my talk by describing our efforts to apply sulfonyl-triazoles for targeting lipid recognition sites on kinases to block metabolic and signaling activity in cells. Broadly, the application of SuTEx for chemical proteomics offers a rational path for identifying tyrosine sites in the human proteome that can be exploited for covalent inhibitor development and potential therapeutic discovery.

Developing tyrosine-targeted covalent inhibitors using sulfonyl-triazoles

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