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

Journal article

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.

Authors: King, O; Li, X; Sakurai, M; Kawamura, A; Rose, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Public Library of Science
• Journal: PloS one
• Volume: 5
• Issue: 11
• Article number: e15535
• Publication date: 2010-01-01
• DOI: 10.1371/journal.pone.0015535
• EISSN: 1932-6203
• ISSN: 1932-6203
• Language: English
• Keywords: Methylation; Enzyme Inhibitors; Hela Cells; Lysine; Dose-Response Relationship, Drug; Hydroxyquinolines; Jumonji Domain-Containing Histone Demethylases; Drug Evaluation, Preclinical; Histones; Mass Spectrometry; Molecular Structure; Humans; Biocatalysis