These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
Design, Synthesis and Characterization of Covalent KDM5 Inhibitors
preprintsubmitted 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.
Read the published paper
in Angewandte Chemie