Format

Send to

Choose Destination
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.

Author information

1
Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
2
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
3
Botnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, NIHR Oxford BRC, University of Oxford, Oxford, OX3 7DQ, UK.
4
Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI, 53711, USA.
5
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, OX3 7FZ, Oxford, UK.
6
Cancer Research (UK) Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK.
7
FRIAS-Freiburg Institute of Advanced Studies, 79104, Freiburg, Germany.

Abstract

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.

KEYWORDS:

KDM5; covalent inhibitors; epigenetics; lysine demethylase

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center