Journal of medicinal chemistry · 2024
Covalent Inhibitors of KEAP1 with Exquisite Selectivity.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Fejes Imre, Markacz Piroska, Tatai Janos, Rudas Monika, Dunkel Petra, Gyuris Mario, Nyerges Miklos, Provost Nicolas, Duvivier Valérie, Delerive Philippe, Martiny Virginie, Bristiel Alexandra, Vidal Brice, Richardson William, Rothweiler Elisabeth M, Tranberg-Jensen Jeppe, Manning Charlotte E, Sweeney Melissa N, Chalk Rod, Huber Kilian V M, Bullock Alex N, Herner Andras, Seedorf Klaus, Vinson Cedric, Weber Csaba, Kotschy Andras
Аннотация
The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting with a phenotypic screen, we identified a new covalent inhibitor chemotype that was optimized to deliver a series of potent and highly selective KEAP1 binders. While the developed compounds showed both cellular and in vivo activity, upregulating antioxidant response element-dependent target genes, they showed no genotoxicity in vitro. The lead compound exhibited broad selectivity in activity-based protein profiling and showed no significant interaction with a panel of commonly studied receptors nor with a broad panel of kinases. The nature of its interaction with KEAP1 and the origin of its selectivity were revealed by X-ray crystallography.