Design, Synthesis and Characterization of Covalent KDM5 Inhibitors
Vazquez-Rodriguez S., Wright M., Rogers C., Cribbs A., Velupillai S., Philpott M., Lee H., Dunford JE., Huber K., Robers MB., Vasta J., Thezenas M-L., Bonham S., Kessler BM., Bennett J., Fedorov O., Raynaud F., Donovan A., Blagg J., Bavetsias V., Oppermann U., Kawamura A., Brennan P.
<jats:p>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.</jats:p>