Covalent modifier drugs have experienced a resurgence of interest with new models for their development. The chemical reaction barriers required for dissociation and association can result in exceptionally high residence times that can be tuned by varying the substituents of the “warhead” functional group of the inhibitor. Targeted Covalent Inhibitors (TCIs) achieve high selectivity and efficacy by optimizing both the non-covalent and covalent interactions with their targets. By targeting non-conserved cysteine residues in the active site for covalent-modification, high selectivity has been achieved in the highly-conserved kinase family. More recently, developed of TCIs has extended beyond cysteine residues, targeting residues like lysine, tyrosine, and methionine. This talk will summarize recent advances in the field, including new computational and experimental methods for discovering covalent modifier drugs.

Targeted covalent inhibition: Review of the field and recent advances

2019 Spring National Meeting

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