Plant Growth Regulator Daminozide Is a Selective Inhibitor of Human KDM2/7 Histone Demethylases
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- 作者：Nathan R. Rose ; Esther C. Y. Woon ; Anthony Tumber ; Louise J. Walport ; Rasheduzzaman Chowdhury ; Xuan Shirley Li ; Oliver N. F. King ; Clarisse Lejeune ; Stanley S. Ng ; Tobias Krojer ; Mun Chiang Chan ; Anna M. Rydzik ; Richard J. Hopkinson ; Ka Hing Che ; Michelle Daniel ; Claire Strain-Damerell ; Carina Gileadi ; Grazyna Kochan ; Ivanhoe K. H. Leung ; James Dunford ; Kar Kheng Yeoh ; Peter J. Ratcliffe ; Nicola Burgess-Brown ; Frank von Delft ; Susanne Muller ; Brian Marsden ; Paul E. Brennan ; Michael A. McDonough ; Udo Oppermann ; Robert J. Klose ; Christopher J. Schofield ; Akane Kawamura
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：July 26, 2012
- 年：2012
- 卷：55
- 期：14
- 页码：6639-6643
- 全文大小：368K
- 年卷期：v.55,no.14(July 26, 2012)
- ISSN：1520-4804
文摘
The JmjC oxygenases catalyze the N-demethylation of N蔚-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.