%0 Journal Article
%A Narayanan, Dilip
%A Tran, Kim T.
%A Pallesen, Jakob S.
%A Solbak, Sara M. Ø.
%A Qin, Yuting
%A Mukminova, Elina
%A Luchini, Martina
%A Vasilyeva, Kristina O.
%A González Chichón, Dorleta
%A Goutsiou, Georgia
%A Poulsen, Cecilie
%A Haapanen, Nanna
%A Popowicz, Grzegorz M.
%A Sattler, Michael
%A Olagnier, David
%A Gajhede, Michael
%A Bach, Anders
%T Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery
%J Journal of medicinal chemistry
%V 65
%N 21
%@ 0022-2623
%C Washington, DC
%I ACS
%M PUBDB-2022-06371
%P 14481 - 14526
%D 2022
%Z Waiting for fulltext 
%X 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<sub>i</sub> = 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36263945
%U <Go to ISI:>//WOS:000885322600001
%R 10.1021/acs.jmedchem.2c00830
%U https://bib-pubdb1.desy.de/record/484604