Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds.

Autor:	Pallesen JS; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Narayanan D; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Tran KT; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Solbak SMØ; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Marseglia G; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.; Food and Drug Department, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy., Sørensen LME; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Høj LJ; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Munafò F; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Carmona RMC; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Garcia AD; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.; École Nationale Supérieure de Chimie de Rennes, 11 Allée de Beaulieu, CS 50837, Rennes Cedex 7 35708, France., Desu HL; The Miami Project to Cure Paralysis, Dept. Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, United States., Brambilla R; The Miami Project to Cure Paralysis, Dept. Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.; Department of Neurobiology Research, Institute of Molecular Medicine, and BRIDGE-Brain Research Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, DK-5000 Odense, Denmark., Johansen TN; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Popowicz GM; Institute of Structural Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry, Technical University of Munich, 85747 Garching, Germany., Sattler M; Institute of Structural Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry, Technical University of Munich, 85747 Garching, Germany., Gajhede M; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Bach A; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Apr 22; Vol. 64 (8), pp. 4623-4661. Date of Electronic Publication: 2021 Apr 05.
DOI:	10.1021/acs.jmedchem.0c02094
Abstrakt:	Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity ( K i = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with K i values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
Databáze:	MEDLINE
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