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001     484604
005     20250724151935.0
024 7 _ |a 10.1021/acs.jmedchem.2c00830
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024 7 _ |a 0022-2623
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024 7 _ |a 0095-9065
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024 7 _ |a 1520-4804
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082 _ _ |a 610
100 1 _ |a Narayanan, Dilip
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245 _ _ |a Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery
260 _ _ |a Washington, DC
|c 2022
|b ACS
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520 _ _ |a 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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700 1 _ |a Tran, Kim T.
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700 1 _ |a Pallesen, Jakob S.
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700 1 _ |a Solbak, Sara M. Ø.
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700 1 _ |a Qin, Yuting
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700 1 _ |a Mukminova, Elina
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700 1 _ |a Luchini, Martina
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700 1 _ |a Vasilyeva, Kristina O.
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700 1 _ |a González Chichón, Dorleta
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700 1 _ |a Goutsiou, Georgia
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700 1 _ |a Poulsen, Cecilie
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700 1 _ |a Haapanen, Nanna
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700 1 _ |a Popowicz, Grzegorz M.
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700 1 _ |a Sattler, Michael
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700 1 _ |a Olagnier, David
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700 1 _ |a Gajhede, Michael
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700 1 _ |a Bach, Anders
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773 _ _ |a 10.1021/acs.jmedchem.2c00830
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|t Journal of medicinal chemistry
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856 4 _ |u https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c00830
856 4 _ |u https://bib-pubdb1.desy.de/record/484604/files/Development%20of%20Noncovalent%20Small-Molecule%20Keap1-Nrf2%20Inhibitors%20by%20Fragment-Based%20Drug%20Discovery.pdf
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