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Design, Synthesis and Characterization of Covalent KDM5 Inhibitors

11 September 2018, Version 1

Abstract

Histone lysine demethylase (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.

Keywords

Covalent Inhibitors
epigenetics
Lysine demethylase
KDM5

Supplementary materials

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Title
SI Covalent KDM5 Inhbitors
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Now Published

Design, Synthesis and Characterization of Covalent KDM5 Inhibitors [opens in a new tab]
Saleta Vazquez‐Rodriguez, Miranda Wright, Catherine M. Rogers, Adam P. Cribbs, Srikannathasan Velupillai, Martin Philpott, Henry Lee, James E. Dunford, Kilian V. M. Huber, Matthew B. Robers, James D. Vasta, Marie‐Laetitia Thezenas, Sarah Bonham, Benedikt Kessler, James Bennett, Oleg Fedorov, Florence Raynaud, Adam Donovan, Julian Blagg, Vassilios Bavetsias, Udo Oppermann, Chas Bountra, Akane Kawamura, Paul E. Brennan journal article
Angewandte Chemie
Online publication date: Dec 07, 2018

Version History

Sep 11, 2018 Version 1

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The content is available under CC BY NC ND 4.0 [opens in a new tab]

DOI

10.26434/chemrxiv.7072592.v1
D O I: 10.26434/chemrxiv.7072592.v1 [opens in a new tab]

Funding

The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and Wellcome [106169/ZZ14/Z]. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 744389, supporting S.V.R. postdoctoral fellowship (TEDCIP). M.W. was supported by the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1). Funding for this project was received from the Oxford NIHR Biomedical Research Unit, Arthritis Research UK (program grant 20522) and the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) (UO) under REA grant agreement n° [609305].

Author’s competing interest statement

No conflicts to declare

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