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Pallesen, J.S.* ; Narayanan, D.* ; Tran, K.T.* ; Solbak, S.M.* ; Marseglia, G.* ; Sørensen, L.M.E.* ; Høj, L.J.* ; Munafò, F.* ; Carmona, R.M.C.* ; Garcia, A.D.* ; Desu, H.L.* ; Brambilla, R.* ; Johansen, T.N.* ; Popowicz, G.M. ; Sattler, M. ; Gajhede, M.* ; Bach, A.*

Deconstructing noncovalent kelch-like ECH-associated protein 1 (Keap1) inhibitors into fragments to reconstruct new potent compounds.

J. Med. Chem. 64, 4623-4661 (2021)
Postprint Research data DOI PMC
Open Access Green
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 (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Macromolecular Crystallography Beamline; Kinetic/affinity Interaction Constants; Fluorescence Polarization; Small-molecule; Oxidative Stress; Diffusion-coefficients; Keap1-nrf2-are Pathway; Nrf2; Binding; Discovery
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 0022-2623
e-ISSN 1520-4804
Journal Journal of Medicinal Chemistry
Quellenangaben Volume: 64, Issue: 8, Pages: 4623-4661 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
Grants Accelerated Early staGe drug dIScovery (AEGIS)
A. P. Moller Foundation for the Advancement of Medical Science
Horslev Foundation
Augustinus Foundation
European Union's Framework Program for Research and Innovation Horizon 2020 (2014-2020) under the Marie SklodowskaCurie Grant
Helmholtz Center Munich
Danish Research Council for Independent Research\Nature and Universe
Drug Research Academy/Lundbeck Foundation
Lundbeck Foundation
DOI 10.1021/acs.jmedchem.0c02094
WOS ID WOS:000644437100019
Scopus ID 85105029797
PubMed ID 33818106
Erfassungsdatum 2021-05-25
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