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.

Human UTY(KDM6C) Is a Male-specific Nϵ-Methyl Lysyl Demethylase

“…Most known KDM inhibitors are competitive with respect to 2OG, and as such, their inhibitor profiles can be similar; however, it is becoming increasingly evident that it is possible to identify inhibitors that discriminate between different subfamilies (26). Recently a small molecule inhibitor of KDM6A/B, GSK-J1, has been described (25).…”

Inhibitors of Enzymes Catalyzing Modifications to Histone Lysine Residues: Structure, Function and Activity

“…The JmjC KDM inhibitors, a separate class of inhibitors from those that target FAD-dependent KDMs, inhibit the removal of methyl-groups from histone lysines by exploiting the iron and α-KG dependent mechanism of JmjC KDMs (Figure 3). For example, daminozide 35 ( Figure 9B) is a selective α-KG competitive inhibitor of KDM2/7 that also chelates the central catalytic iron ion between its hydrazide carbonyl oxygen and dimethylamino nitrogen [159]. Modeling the active site of KDM2/7, the daminozide structure was optimized with an α-KG mimic and a longer alkyl chain 36 to serve as a lead structure in the development of more potent and selective KDM2/7 inhibitors [160].…”

Advances in the development of histone lysine demethylase inhibitors

“…The plant growth regulator daminozide is a KDM inhibitor selective for the KDM2/7 subfamily (IC50 values are 0.55, 1.5 and 2.1 mM for PHF8, KDM2A and KDM7A respectively and exhibits !60-fold selectivity for KDM2/ 7 demethylases over other histone demethylases and 2-oxoglurate oxygenases (IC50 > 100 mM)[19]. Treatment with 2 mM daminozide incremented H3K9 methylation in melanoma cells to similar levels as siRNA mediated KDM7 knockdown[20], reflecting good cell penetration.…”