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

页码：9451 / 9456

页数：6

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