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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)