Discovery of a Highly Selective Cell-Active Inhibitor of the Histone Lysine Demethylases KDM2/7

  • Angew Chem Int Ed Engl. 2017 Dec 4;56(49):15555-15559. doi: 10.1002/anie.201706788.
Philip A Gerken  1 ,  Jamie R Wolstenhulme  1 ,  Anthony Tumber  2 ,  Stephanie B Hatch  2 ,  Yijia Zhang  1 ,  Susanne Müller  2 ,  Shane A Chandler  1 ,  Barbara Mair  2 ,  Fengling Li  3 ,  Sebastian M B Nijman  2 ,  Rebecca Konietzny  2 ,  Tamas Szommer  2 ,  Clarence Yapp  2 ,  Oleg Fedorov  2 ,  Justin L P Benesch  1 ,  Masoud Vedadi  3 ,  Benedikt M Kessler  2 ,  Akane Kawamura  1 ,  Paul E Brennan  2 ,  Martin D Smith  1
Affiliations
  • 1. Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
  • 2. Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.
  • 3. Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
PMID: 28976073 DOI: 10.1002/anie.201706788
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.

Keywords
asymmetric catalysis; epigenetics; inhibitors; lysine demethylases.
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