A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases.

J Am Chem Soc
Authors
Xuelai Luo
Yongxiang Liu
Stefan Kubicek
Johanna Myllyharju
Anthony Tumber
Stanley Ng
Ka Che
Jessica Podoll
Tom Heightman
Udo Oppermann
Stuart Schreiber
Xiang Wang
Keywords
Humans
Enzyme Inhibitors
Nuclear Proteins
Cell Line, Tumor
Drug Design
Substrate Specificity
Inhibitory Concentration 50
Esters
Histone Demethylases
Jumonji Domain-Containing Histone Demethylases
Muscle Development
Prodrugs
Abstract

Histone methylations are important chromatin marks that regulate gene expression, genomic stability, DNA repair, and genomic imprinting. Histone demethylases are the most recent family of histone-modifying enzymes discovered. Here, we report the characterization of a small-molecule inhibitor of Jumonji C domain-containing histone demethylases. The inhibitor derives from a structure-based design and preferentially inhibits the subfamily of trimethyl lysine demethylases. Its methyl ester prodrug, methylstat, selectively inhibits Jumonji C domain-containing his-tone demethylases in cells and may be a useful small-molecule probe of chromatin and its role in epigenetics.
Year of Publication
2011
Journal
J Am Chem Soc
Volume
133
Issue
24
Pages
9451-6
Date Published
2011 Jun 22
ISSN
1520-5126
DOI
10.1021/ja201597b
PubMed ID
21585201
PubMed Central ID
PMC3133600
Links
Grant list
R37 GM038627 / GM / NIGMS NIH HHS / United States
R01 GM038627 / GM / NIGMS NIH HHS / United States
Canadian Institutes of Health Research / Canada
Howard Hughes Medical Institute / United States
GM38627 / GM / NIGMS NIH HHS / United States
R01 GM098390 / GM / NIGMS NIH HHS / United States
R01 GM038627-20 / GM / NIGMS NIH HHS / United States
Wellcome Trust / United Kingdom

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