National Center for
4AI8: FACTOR INHIBITING HIF-1 ALPHA IN COMPLEX WITH DAMINOZIDE
J. Med. Chem. (2012) 55 p.6639-6643
The JmjC oxygenases catalyze the N-demethylation of N(epsilon)-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.