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Design, Synthesis and Characterization of Covalent KDM5 Inhibitors

Lookup NU author(s): Professor Akane Kawamura

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.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.

Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Angewandte Chemie - International Edition

Year: 2019

Volume: 58

Issue: 2

Pages: 515-519

Print publication date: 08/01/2019

Online publication date: 07/12/2018

Acceptance date: 15/11/2018

Date deposited: 10/10/2019

ISSN (print): 1433-7851

ISSN (electronic): 1521-3773

Publisher: Wiley-VCH Verlag

URL: https://doi.org/10.1002/anie.201810179

DOI: 10.1002/anie.201810179

PubMed id: 30431220

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