Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors

DOI: 10.1371/journal.pone.0015535
PMID: 21124847

Authors: Oliver N. F. King (University of Oxford) , Xuan Shirley Li (University of Oxford) , Masaaki Sakurai (National Human Genome Research Institute, National Institutes of Health) , Akane Kawamura (University of Oxford) , Nathan R. Rose (University of Oxford) , Stanley S. Ng (University of Oxford) , Amy M. Quinn (National Human Genome Research Institute, National Institutes of Health) , Ganesha Rai (National Human Genome Research Institute, National Institutes of Health) , Bryan Mott (National Human Genome Research Institute, National Institutes of Health) , Paul Beswick (Structural Genomics Consortium, University of Oxford) , Robert Klose (University of Oxford) , Udo Oppermann (Structural Genomics Consortium, University of Oxford) , Ajit Jadhav (National Human Genome Research Institute, National Institutes of Health) , Tom Heightman (Structural Genomics Consortium, University of Oxford) , David J. Maloney (National Human Genome Research Institute, National Institutes of Health) , Christopher J. Schofield (University of Oxford) , Anton Simeonov (National Human Genome Research Institute, National Institutes of Health)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos One

State: Published (Approved)
Published: November 2010

Abstract: Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N (epsilon)-Methylation of lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. N (epsilon)-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors.

Journal Keywords: Dose-Response; Drug; Drug; Preclinical; Enzyme; HeLa; Histones; Humans; Hydroxyquinolines; Jumonji; Lysine; Mass; Methylation; Molecular Structure

Diamond Keywords: Epigenetics; Enzymes

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 30/11/2010 08:33

Documents:
file-3.pdf

Discipline Tags:

Health & Wellbeing Genetics Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)