Covalent Inhibitors of KEAP1 with Exquisite Selectivity

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 wi...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2024-12, Vol.67 (23), p.21208-21222
Main Authors: 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
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c02019