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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.

Original publication

DOI

10.1002/anie.201706788

Type

Journal article

Journal

Angew Chem Int Ed Engl

Publication Date

04/12/2017

Volume

56

Pages

15555 - 15559

Keywords

asymmetric catalysis, epigenetics, inhibitors, lysine demethylases, Dose-Response Relationship, Drug, Drug Discovery, Enzyme Inhibitors, F-Box Proteins, HeLa Cells, Humans, Jumonji Domain-Containing Histone Demethylases, Molecular Structure, Structure-Activity Relationship