Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases

Abstract

The JmjC oxygenases catalyze the N-demethylation of N ε- methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups. © 2012 American Chemical Society.