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Design, Synthesis and Characterization of Covalent KDM5 Inhibitors

submitted on 11.09.2018, 12:43 and posted on 11.09.2018, 14:36 by Saleta Vazquez-Rodriguez, Miranda Wright, Catherine Rogers, Adam Cribbs, Srikannathasan Velupillai, Martin Philpott, Henry Lee, James E. Dunford, Kilian Huber, Matthew B. Robers, Jim Vasta, Marie-Laetitia Thezenas, Sarah Bonham, Benedikt M. Kessler, James Bennett, Oleg Fedorov, Florence Raynaud, Adam Donovan, Julian Blagg, Vassilios Bavetsias, Udo Oppermann, Akane Kawamura, Paul Brennan
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.


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].


Email Address of Submitting Author


University of Oxford


United Kingdom

ORCID For Submitting Author


Declaration of Conflict of Interest

No conflicts to declare