TY  - JOUR
AU  - Narayanan, Dilip
AU  - Tran, Kim T.
AU  - Pallesen, Jakob S.
AU  - Solbak, Sara M. Ø.
AU  - Qin, Yuting
AU  - Mukminova, Elina
AU  - Luchini, Martina
AU  - Vasilyeva, Kristina O.
AU  - González Chichón, Dorleta
AU  - Goutsiou, Georgia
AU  - Poulsen, Cecilie
AU  - Haapanen, Nanna
AU  - Popowicz, Grzegorz M.
AU  - Sattler, Michael
AU  - Olagnier, David
AU  - Gajhede, Michael
AU  - Bach, Anders
TI  - Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery
JO  - Journal of medicinal chemistry
VL  - 65
IS  - 21
SN  - 0022-2623
CY  - Washington, DC
PB  - ACS
M1  - PUBDB-2022-06371
SP  - 14481 - 14526
PY  - 2022
N1  - Waiting for fulltext 
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36263945
UR  - <Go to ISI:>//WOS:000885322600001
DO  - DOI:10.1021/acs.jmedchem.2c00830
UR  - https://bib-pubdb1.desy.de/record/484604
ER  -