Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery
Copyright policy )Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery
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 (Ki = 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.
- University of California, San Diego United States
- Deutsches Elektronen-Synchrotron DESY Germany
- Aarhus University Denmark
- Helmholtz Zentrum München Germany
- Technical University of Munich Germany
COMPOUND INTERFERENCE, Kelch-Like ECH-Associated Protein 1, NRF2 ACTIVATORS, NF-E2-Related Factor 2, MACROMOLECULAR CRYSTALLOGRAPHY BEAMLINE, DIFFUSION-COEFFICIENTS, PROTEIN-PROTEIN INTERACTION, Kelch-Like ECH-Associated Protein 1/metabolism, FLUORESCENCE POLARIZATION, Oxidative Stress, NF-E2-Related Factor 2/metabolism, AMINO ESTERS, BINDING, Drug Discovery, Drug Discovery/methods, OXIDATIVE STRESS, KINETIC/AFFINITY INTERACTION CONSTANTS, info:eu-repo/classification/ddc/610, Protein Binding
COMPOUND INTERFERENCE, Kelch-Like ECH-Associated Protein 1, NRF2 ACTIVATORS, NF-E2-Related Factor 2, MACROMOLECULAR CRYSTALLOGRAPHY BEAMLINE, DIFFUSION-COEFFICIENTS, PROTEIN-PROTEIN INTERACTION, Kelch-Like ECH-Associated Protein 1/metabolism, FLUORESCENCE POLARIZATION, Oxidative Stress, NF-E2-Related Factor 2/metabolism, AMINO ESTERS, BINDING, Drug Discovery, Drug Discovery/methods, OXIDATIVE STRESS, KINETIC/AFFINITY INTERACTION CONSTANTS, info:eu-repo/classification/ddc/610, Protein Binding
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