9F2P
Crystal structure of Keap1 kelch domain in complex with a fluorenone-based small molecule inhibitor at 1.36A resolution
This is a non-PDB format compatible entry.
Summary for 9F2P
| Entry DOI | 10.2210/pdb9f2p/pdb |
| Descriptor | Kelch-like ECH-associated protein 1, (R)-2-(3-(((4-methoxyphenyl)sulfonamido)methyl)phenyl)-2-(9-oxo-9H-fluorene-4-carboxamido)acetate, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | keap1, nrf2, oxidative stress, inhibitor, peptide binding protein |
| Biological source | Mus musculus (house mouse) |
| Total number of polymer chains | 1 |
| Total formula weight | 35475.13 |
| Authors | Narayanan, D.,Bach, A.,Gajhede, M. (deposition date: 2024-04-23, release date: 2024-10-30, Last modification date: 2024-11-27) |
| Primary citation | Qin, Y.,Poulsen, C.,Narayanan, D.,Chan, C.B.,Chen, X.,Montes, B.R.,Tran, K.T.,Mukminova, E.,Lin, C.,Gajhede, M.,Bullock, A.N.,Olagnier, D.,Bach, A. Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors. J.Med.Chem., 67:18828-18864, 2024 Cited by PubMed Abstract: Inhibition 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 ( = 2.9 μM), a new series of tetrahydroisoquinoline-based Keap1 inhibitors with up to 223-fold improvement in binding affinity (, = 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. PubMed: 39418396DOI: 10.1021/acs.jmedchem.4c01221 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.36 Å) |
Structure validation
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