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

  • J Med Chem. 2012 Jul 26;55(14):6639-43. doi: 10.1021/jm300677j.
Nathan R Rose  1 ,  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
Affiliations
  • 1. Epigenetic Regulation of Chromatin Function Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
PMID: 22724510 DOI: 10.1021/jm300677j
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.

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