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- Title
Discovery of a Highly Selective Cell-Active Inhibitor of the Histone Lysine Demethylases KDM2/7.
- Authors
Gerken, Philip A.; Wolstenhulme, Jamie R.; Tumber, Anthony; Hatch, Stephanie B.; Zhang, Yijia; Müller, Susanne; Chandler, Shane A.; Mair, Barbara; Li, Fengling; Nijman, Sebastian M. B.; Konietzny, Rebecca; Szommer, Tamas; Yapp, Clarence; Fedorov, Oleg; Benesch, Justin L. P.; Vedadi, Masoud; Kessler, Benedikt M.; Kawamura, Akane; Brennan, Paul E.; Smith, Martin D.
- Abstract
Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell-permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure-activity relationships, leading to the development of a small molecule with around 75-fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.
- Subjects
HISTONE demethylases; ENZYME inhibitors; EPIGENETICS; GENE expression; STRUCTURE-activity relationships
- Publication
Angewandte Chemie, 2017, Vol 129, Issue 49, p15761
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201706788