7OF8

Keap1 kelch domain bound to a small molecule fragment

Summary for 7OF8

• Entry DOI: 10.2210/pdb7of8/pdb
• Descriptor: Kelch-like ECH-associated protein 1, (2~{S})-2-cyclopentyl-2-oxidanyl-2-phenyl-ethanoic acid (3 entities in total)
• Functional Keywords: keap1, nrf2, oxidative stress, small molecule complex, maybridge, peptide binding protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 33582.56

Authors

Narayanan, D.,Bach, A.,Gajhede, M. (deposition date: 2021-05-04, release date: 2022-11-02, Last modification date: 2024-01-31)

Primary citation

Narayanan, D.,Tran, K.T.,Pallesen, J.S.,Solbak, S.M.O.,Qin, Y.,Mukminova, E.,Luchini, M.,Vasilyeva, K.O.,Gonzalez Chichon, D.,Goutsiou, G.,Poulsen, C.,Haapanen, N.,Popowicz, G.M.,Sattler, M.,Olagnier, D.,Gajhede, M.,Bach, A.
Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery.
J.Med.Chem., 65:14481-14526, 2022

PubMed Abstract: Targeting the protein-protein interaction (PPI) between the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its repressor, Kelch-like ECH-associated protein 1 (Keap1), constitutes a promising strategy for treating diseases involving oxidative stress and inflammation. Here, a fragment-based drug discovery (FBDD) campaign resulted in novel, high-affinity ( = 280 nM), and cell-active noncovalent small-molecule Keap1-Nrf2 PPI inhibitors. We screened 2500 fragments using orthogonal assays─fluorescence polarization (FP), thermal shift assay (TSA), and surface plasmon resonance (SPR)─and validated the hits by saturation transfer difference (STD) NMR, leading to 28 high-priority hits. Thirteen co-structures showed fragments binding mainly in the P4 and P5 subpockets of Keap1's Kelch domain, and three fluorenone-based fragments featuring a novel binding mode were optimized by structure-based drug discovery. We thereby disclose several fragment hits, including their binding modes, and show how FBDD can be performed to find new small-molecule Keap1-Nrf2 PPI inhibitors.

PubMed: 36263945
DOI: 10.1021/acs.jmedchem.2c00830

Experimental method

X-RAY DIFFRACTION (1.78 Å)