2. Academic Validation
  3. Discovery of a Highly Selective Cell-Active Inhibitor of the Histone Lysine Demethylases KDM2/7

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

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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