Plant Growth Regulator Daminozide Is a Selective Inhibitor of Human KDM2/7 Histone Demethylases

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 daminozid...

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Veröffentlicht in:	Journal of medicinal chemistry 2012-07, Vol.55 (14), p.6639-6643
Hauptverfasser:	Rose, Nathan R, Woon, Esther C. Y, Tumber, Anthony, Walport, Louise J, Chowdhury, Rasheduzzaman, Li, Xuan Shirley, King, Oliver N. F, Lejeune, Clarisse, Ng, Stanley S, Krojer, Tobias, Chan, Mun Chiang, Rydzik, Anna M, Hopkinson, Richard J, Che, Ka Hing, Daniel, Michelle, Strain-Damerell, Claire, Gileadi, Carina, Kochan, Grazyna, Leung, Ivanhoe K. H, Dunford, James, Yeoh, Kar Kheng, Ratcliffe, Peter J, Burgess-Brown, Nicola, von Delft, Frank, Muller, Susanne, Marsden, Brian, Brennan, Paul E, McDonough, Michael A, Oppermann, Udo, Klose, Robert J, Schofield, Christopher J, Kawamura, Akane
Format:	Artikel
Sprache:	eng
Schlagworte:	Enzyme Inhibitors - pharmacology Humans Inhibitory Concentration 50 Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors Jumonji Domain-Containing Histone Demethylases - chemistry Jumonji Domain-Containing Histone Demethylases - metabolism Models, Molecular Plant Growth Regulators - pharmacology Protein Conformation Substrate Specificity Succinates - pharmacology
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Beschreibung
Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm300677j