Reversible Covalent Inhibitors: From Serendipity to Clinical Trials

Drugs with prolonged, on-target residence time often show superior efficacy. An increasingly popular strategy for increasing residence time is to incorporate a weak electrophile that forms an irreversible covalent bond with a nonconserved cysteine. However, achieving exquisite kinetic selectivity for a single cysteine, out of thousands of competing cysteines in the proteome, is extremely difficult. In addition, many proteins lack an accessible cysteine, motivating the search for small-molecule ligands that covalently target other nucleophilic residues. In this lecture, I will describe our efforts to explore electrophilic chemistry space. Our experiments, which integrate chemical synthesis, protein/ligand crystallography, and mass spectrometry, have revealed unexpected mechanisms for tuning drug-target residence time via reversible covalent interactions.

Speaker: Jack Taunton, University of California, San Francisco

Andrew Braisted Award Lecture