PuSH - Publication Server of Helmholtz Zentrum München: Development of noncovalent small-molecule Keap1-Nrf2 inhibitors by fragment-based drug discovery.

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Narayanan, D.* ; Tran, K.T.* ; Pallesen, J.S.* ; Solbak, S.M.* ; Qin, Y.* ; Mukminova, E.* ; Luchini, M.* ; Vasilyeva, K.O.* ; González Chichón, 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)

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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 (K_i = 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.

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