Journal Article

PUBDB-2022-06371

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery

Narayanan, D. ; Tran, K. T. ; Pallesen, J. S. ; Solbak, S. M. Ø. ; 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. (Corresponding author)

2022
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.2c00830

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 (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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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)
2. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2022

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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