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Angew Chem Int Ed Engl. 2017 Dec 4;56(49):15555-15559. doi: 10.1002/anie.201706788. Epub 2017 Nov 7.

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

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Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.


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.


asymmetric catalysis; epigenetics; inhibitors; lysine demethylases

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