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

DOI: 10.1021/jm300677j
PMID: 22724510

Authors: Nathan Rose (University of Oxford) , Esther C. Y. Woon (University of Oxford) , Anthony Tumber (Structural Genomics Consortium, University of Oxford) , Louise J. Walport (University of Oxford) , Rasheduzzaman Chowdhury (University of Oxford) , Xuan Shirley Li (University of Oxford) , Oliver N. F. King (University of Oxford) , Clarisse Lejeune (Structural Genomics Consortium, University of Oxford) , Stanley Ng (Structural Genomics Consortium, University of Oxford) , Tobias Krojer (Structural Genomics Consortium, University of Oxford) , Mun Chiang Chan (Structural Genomics Consortium, University of Oxford) , Anna M. Rydzik (University of Oxford) , Richard J. Hopkinson (University of Oxford) , Ka Hing Che (Structural Genomics Consortium, University of Oxford) , Michelle Daniel (Structural Genomics Consortium, University of Oxford) , Claire Strain-Damerell (Structural Genomics Consortium, University of Oxford) , Carina Gileadi (Structural Genomics Consortium, University of Oxford) , Grazyna Kochan (Structural Genomics Consortium, University of Oxford) , Ivanhoe K. H. Leung (University of Oxford) , James Dunford (University of Oxford) , Kar Kheng Yeo (University of Oxford) , Peter J. Ratcliffe (University of Oxford) , Nicola Burgess-Brown (Structural Genomics Consortium, University of Oxford) , Frank Von Delft (Structural Genomics Consortium, University of Oxford) , Susanne Muller (Structural Genomics Consortium, University of Oxford) , Brian Marsden (Structural Genomics Consortium, University of Oxford) , Paul. E. Brennan (Structural Genomics Consortium, University of Oxford) , Michael A. Mcdonough (University of Oxford) , Udo Oppermann (University of Oxford) , Robert J. Klose (University of Oxford) , Christopher J. Schofield (University of Oxford) , Akane Kawamura (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 55 (14) , PAGES 6639 - 6643

State: Published (Approved)
Published: July 2012
Diamond Proposal Number(s): 7495

Abstract: The JmjC oxygenases catalyze the N-demethylation of Nε-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.

Journal Keywords: Humans; Inhibitory; Jumonji; Models; Molecular; Plant; Protein; Substrate; Succinates

Subject Areas: Medicine, Biology and Bio-materials, Chemistry


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 28/03/2013 14:44

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)