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Angew Chem Int Ed Engl. 2019 Jan 8;58(2):515-519. doi: 10.1002/anie.201810179. Epub 2018 Dec 7.

Design, Synthesis and Characterization of Covalent KDM5 Inhibitors.

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Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Botnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, NIHR Oxford BRC, University of Oxford, Oxford, OX3 7DQ, UK.
Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI, 53711, USA.
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, OX3 7FZ, Oxford, UK.
Cancer Research (UK) Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK.
FRIAS-Freiburg Institute of Advanced Studies, 79104, Freiburg, Germany.


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.


KDM5; covalent inhibitors; epigenetics; lysine demethylase

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