A Selective Inhibitor and Probe of the Cellular Functions of Jumonji C Domain-Containing Histone Demethylases

被引：118
|
作者：
Luo, Xuelai [1 ]
Liu, Yongxiang [1 ]
Kubicek, Stefan [2 ,3 ,4 ,5 ]
Myllyharju, Johanna [6 ]
Tumber, Anthony [7 ]
Ng, Stanley [7 ,8 ]
Che, Ka Hing [7 ,8 ]
Podoll, Jessica [1 ]
Heightman, Tom D. [7 ]
Oppermann, Udo [7 ,8 ]
Schreiber, Stuart L. [2 ,3 ,4 ]
Wang, Xiang [1 ]
机构：
[1] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA
[2] Broad Inst Harvard, Howard Hughes Med Inst, Cambridge, MA 02142 USA
[3] MIT, Cambridge, MA 02142 USA
[4] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA
[5] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria
[6] Univ Oulu, Dept Med Biochem & Mol Biol, Bioctr Oulu, Oulu Ctr Cell Matrix Res, FIN-90014 Oulu, Finland
[7] Univ Oxford, Struct Genom Consortium, Headington OX3 7DQ, England
[8] Oxford Biomed Res Unit, NIHR, Botnar Res Ctr, Oxford OX3 7LD, England
来源：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2011年 / 133卷 / 24期
基金：
英国惠康基金;
关键词：
OXYGEN SENSING PATHWAY; LYSINE DEMETHYLASES; PROLYL; 4-HYDROXYLASES; SUBSTRATE-SPECIFICITY; STRUCTURAL INSIGHTS; MODIFYING ENZYMES; FAMILY; CELLS; LSD1; DEACETYLASES;
D O I：
10.1021/ja201597b
中图分类号：
O6 [化学];
学科分类号：
0703 ;
摘要：
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 histone demethylases in cells and may be a useful small-molecule probe of chromatin and its role in epigenetics.
引用
收藏
页码：9451 / 9456
页数：6
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