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Design, Synthesis and Characterization of Covalent KDM5 Inhibitors
Author(s) -
VazquezRodriguez Saleta,
Wright Miranda,
Rogers Catherine M.,
Cribbs Adam P.,
Velupillai Srikannathasan,
Philpott Martin,
Lee Henry,
Dunford James E.,
Huber Kilian V. M.,
Robers Matthew B.,
Vasta James D.,
Thezenas MarieLaetitia,
Bonham Sarah,
Kessler Benedikt,
Bennett James,
Fedorov Oleg,
Raynaud Florence,
Donovan Adam,
Blagg Julian,
Bavetsias Vassilios,
Oppermann Udo,
Bountra Chas,
Kawamura Akane,
Brennan Paul E.
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201810179
Subject(s) - chemistry , covalent bond , h3k4me3 , histone , biochemistry , cysteine , gene expression , lysine , gene , microbiology and biotechnology , biology , enzyme , promoter , amino acid , organic chemistry
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.