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. Here we describe the discovery of a new class of inhibitor that is highly selective towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore chemical space and accelerate investigation of key structure-activity relationships, leading to the development of a small molecule with ≥75-fold selectivity towards KDM2A/7A vs other KDMs, as well as cellular activity at low micromolar concentrations.
