9ETW

BTB domain of KLHL26

Summary for 9ETW

• Entry DOI: 10.2210/pdb9etw/pdb
• Descriptor: Kelch-like protein 26, 1,2-ETHANEDIOL (3 entities in total)
• Functional Keywords: btb, klhl26, keap1, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 28106.59

Authors

Richardson, W.,Bullock, A.N.,Rothweiler, E.M.,Manning, C.E.,Sweeney, M.N.,Chalk, R.,Huber, K.V.M. (deposition date: 2024-03-27, release date: 2024-12-11)

Primary citation

Fejes, I.,Markacz, P.,Tatai, J.,Rudas, M.,Dunkel, P.,Gyuris, M.,Nyerges, M.,Provost, N.,Duvivier, V.,Delerive, P.,Martiny, V.,Bristiel, A.,Vidal, B.,Richardson, W.,Rothweiler, E.M.,Tranberg-Jensen, J.,Manning, C.E.,Sweeney, M.N.,Chalk, R.,Huber, K.V.M.,Bullock, A.N.,Herner, A.,Seedorf, K.,Vinson, C.,Weber, C.,Kotschy, A.
Covalent Inhibitors of KEAP1 with Exquisite Selectivity.
J.Med.Chem., 2024

PubMed Abstract: 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.

PubMed: 39572012
DOI: 10.1021/acs.jmedchem.4c02019

Experimental method

X-RAY DIFFRACTION (1.51 Å)