Design, Synthesis and Characterization of Covalent KDM5 Inhibitors.
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ICR Authors
Authors
Vazquez-Rodriguez, S
Wright, M
Rogers, CM
Cribbs, AP
Velupillai, S
Philpott, M
Lee, H
Dunford, JE
Huber, KVM
Robers, MB
Vasta, JD
Thezenas, M-L
Bonham, S
Kessler, B
Bennett, J
Fedorov, O
Raynaud, F
Donovan, A
Blagg, J
Bavetsias, V
Oppermann, U
Bountra, C
Kawamura, A
Brennan, PE
Wright, M
Rogers, CM
Cribbs, AP
Velupillai, S
Philpott, M
Lee, H
Dunford, JE
Huber, KVM
Robers, MB
Vasta, JD
Thezenas, M-L
Bonham, S
Kessler, B
Bennett, J
Fedorov, O
Raynaud, F
Donovan, A
Blagg, J
Bavetsias, V
Oppermann, U
Bountra, C
Kawamura, A
Brennan, PE
Document Type
Journal Article
Date
2019-01-08
Date Accepted
2018-10-15
Abstract
Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor development. Here we report potent and selective KDM5 covalent inhibitors designed to target cysteine residues only present in the KDM5 sub-family. The covalent binding to the targeted proteins was confirmed by MS and time-dependent inhibition. Additional competition assays show that compounds were non 2-OG competitive. Target engagement and ChIP-seq analysis showed that the compounds inhibited the KDM5 members in cells at nano- to micromolar levels and induce a global increase of the H3K4me3 mark at transcriptional start sites.
Citation
Angewandte Chemie (International ed. in English), 2019, 58 (2), pp. 515 - 519
Source Title
Publisher
WILEY-V C H VERLAG GMBH
ISSN
1433-7851
eISSN
1521-3773
Collections
Research Team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Medicinal Chemistry 1