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000484604 1001_ $$aNarayanan, Dilip$$b0
000484604 245__ $$aDevelopment of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery
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000484604 520__ $$aTargeting 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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000484604 7001_ $$aTran, Kim T.$$b1
000484604 7001_ $$00000-0001-8862-3525$$aPallesen, Jakob S.$$b2
000484604 7001_ $$00000-0003-0233-7160$$aSolbak, Sara M. Ø.$$b3
000484604 7001_ $$aQin, Yuting$$b4
000484604 7001_ $$aMukminova, Elina$$b5
000484604 7001_ $$aLuchini, Martina$$b6
000484604 7001_ $$aVasilyeva, Kristina O.$$b7
000484604 7001_ $$00000-0002-5813-5464$$aGonzález Chichón, Dorleta$$b8
000484604 7001_ $$aGoutsiou, Georgia$$b9
000484604 7001_ $$aPoulsen, Cecilie$$b10
000484604 7001_ $$aHaapanen, Nanna$$b11
000484604 7001_ $$aPopowicz, Grzegorz M.$$b12
000484604 7001_ $$00000-0002-1594-0527$$aSattler, Michael$$b13
000484604 7001_ $$00000-0001-6912-0674$$aOlagnier, David$$b14
000484604 7001_ $$00000-0001-9864-2287$$aGajhede, Michael$$b15
000484604 7001_ $$00000-0003-4305-9910$$aBach, Anders$$b16$$eCorresponding author
000484604 773__ $$0PERI:(DE-600)1491411-6$$a10.1021/acs.jmedchem.2c00830$$gp. acs.jmedchem.2c00830$$n21$$p14481 - 14526$$tJournal of medicinal chemistry$$v65$$x0022-2623$$y2022
000484604 8564_ $$uhttps://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c00830
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