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 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.
Authors
- Petra Dunkel (ORCID: https://orcid.org/0000-0001-5445-8357)
- Valérie Duvivier (ORCID: https://orcid.org/0000-0002-1162-3938)
- Charlotte E. Manning
- Klaus Seedorf (ORCID: https://orcid.org/0000-0002-0383-089X)
- William Richardson (ORCID: https://orcid.org/0000-0003-0674-4898)
- András Kotschy (ORCID: https://orcid.org/0000-0002-7675-3864)
- Nicolas Provost
- Philippe Delerive (ORCID: https://orcid.org/0000-0002-8649-9724)
- Piroska Markacz
- Miklós Nyerges (ORCID: https://orcid.org/0000-0001-9433-6872)
- Cédric Vinson (ORCID: https://orcid.org/0000-0001-8067-4766)
- Imre Fejes (ORCID: https://orcid.org/0000-0003-1337-0169)
- Márió Gyuris (ORCID: https://orcid.org/0000-0002-2259-5792)
- Csaba Wéber
- Virginie Martiny (ORCID: https://orcid.org/0000-0002-6866-3957)
- K. Huber (ORCID: https://orcid.org/0000-0002-1103-5300)
- János Tatai
- R. Chalk (ORCID: https://orcid.org/0000-0002-9942-2339)
- Alex N. Bullock (ORCID: https://orcid.org/0000-0001-6757-0436)
- Mónika Rudas
- Elisabeth M. Rothweiler (ORCID: https://orcid.org/0000-0003-3303-2044)
- Alexandra Bristiel
- Jeppe Tranberg-Jensen
- Melissa N. Sweeney
- Brice Vidal
- Andras Herner
Institutions
- Angkor Hospital for Children (KH)
- Nuffield Orthopaedic Centre (GB)
- University of Oxford (GB)
- Servier (France) (FR)
- Institut des Hautes Études Scientifiques (FR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02019
- Citations
- 3
- Primary Topic
- Genomics, phytochemicals, and oxidative stress
- Type
- article
- Field-Weighted Citation Impact
- 0.70