9etx

KEAP1 BTB in complex with compound 23

spinqualitylabelsall models 9etx, resolution 2.34Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9etx is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.34Å Ligands: A1H67 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KEAP1_HUMAN Publication Abstract from PubMed 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. Covalent Inhibitors of KEAP1 with Exquisite Selectivity.,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 EM, Tranberg-Jensen J, Manning CE, Sweeney MN, Chalk R, Huber KVM, Bullock AN, Herner A, Seedorf K, Vinson C, Weber C, Kotschy A J Med Chem. 2024 Nov 21. doi: 10.1021/acs.jmedchem.4c02019. PMID:39572012 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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