9f2p
Crystal structure of Keap1 kelch domain in complex with a fluorenone-based small molecule inhibitor at 1.36A resolution
Structural highlights
FunctionKEAP1_MOUSE Retains NFE2L2/NRF2 in the cytosol. Functions as substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1. Targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. May also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome (By similarity).[1] [2] Publication Abstract from PubMedInhibition of the protein-protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) has been recognized as an attractive approach for treating oxidative stress-related diseases. Here, we present a new series of noncovalent Keap1-Nrf2 inhibitors developed by a conformational restriction strategy of our fluorenone-based compounds previously identified by fragment-based drug discovery. The design was guided by X-ray cocrystal structures, and the subsequent optimization process aimed at improving affinity, cellular activity, and metabolic stability. From the noncyclic compound 7 (K(i) = 2.9 muM), a new series of tetrahydroisoquinoline-based Keap1 inhibitors with up to 223-fold improvement in binding affinity (57, K(i) = 13 nM), better metabolic stability, and enhanced cellular activity was obtained. In addition, the compounds showed selectivity for the Keap1 Kelch domain across a panel of 15 homologous proteins. We thereby demonstrate the utility of cyclic rigidification in the design of potent and more drug-like Keap1-Nrf2 inhibitors. Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors.,Qin Y, Poulsen C, Narayanan D, Chan CB, Chen X, Montes BR, Tran KT, Mukminova E, Lin C, Gajhede M, Bullock AN, Olagnier D, Bach A J Med Chem. 2024 Oct 17. doi: 10.1021/acs.jmedchem.4c01221. PMID:39418396[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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