Covalent Inhibitors\nof KEAP1 with Exquisite Selectivity

The NRF2-KEAP1 interaction is central for cytoprotection\nagainst\nstresses, giving it high clinical significance. Covalent modification\nof KEAP1 is an efficient approach, but the covalent inhibitors used\nin the clinic carry undesired side effects originating in their moderate\nselectivity. Starting with a phenotypic screen, we identified a new\ncovalent inhibitor chemotype that was optimized to deliver a series\nof potent and highly selective KEAP1 binders. While the developed\ncompounds showed both cellular and in vivo activity, upregulating\nantioxidant response element-dependent target genes, they showed no\ngenotoxicity in vitro. The lead compound exhibited broad selectivity\nin activity-based protein profiling and showed no significant interaction\nwith a panel of commonly studied receptors nor with a broad panel\nof kinases. The nature of its interaction with KEAP1 and the origin\nof its selectivity were revealed by X-ray crystallography.