Covalent Fragment Screening with Chemoproteomics: KEAP1 Engagers with an Unusual Warhead

Nrf2/KEAP1 modulation has been a hotly pursued pathway since the 2012 report that dimethyl fumarate and its metabolite monomethyl fumarate protect CNS neurons via up-regulation of Nrf2-dependent activities. Compounds with greater selectivity than dimethyl fumarate have been sought after for many years, culminating with a recent approval for a reversible covalent KEAP1 inhibitor and Nrf2 activator, omaveloxolone. Vividion recently disclosed their efforts to identify a selective covalent KEAP1 inhibitor, VVD-702, which is active in various in vivo settings.  This ACS Spring 2024 disclosure is an excellent case study for covalent hit finding using chemoproteomics, covalent compound optimization, and the use of an uncommon but surprisingly stable covalent warhead.