Quantitative High-Throughput Screening Identifies 8-Hydroxyquinolines as Cell-Active Histone Demethylase Inhibitors

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

Authors: Oliver King (University of Oxford) , Xuan Shirley LI , Masaaki Sakurai , Akane Kawamura , Nathan Rose (University of Oxford) , Stanley Ng (University of Oxford) , Amy Quinn , Ganesha Rai , Bryan Mott , Paul Beswick , Robert Klose , Udo Oppermann , Ajit Jadhav , Tom Heightman , David Maloney , Christopher Schofield , Anton Simeonov
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

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography