Development of Cell-Active N6-Methyladenosine RNA Demethylase FTO Inhibitor

被引：482

作者：

Chen, Baoen ^{[1
]}

Ye, Fei ^{[1
]}

Yu, Lu ^{[2
]}

Jia, Guifang ^{[3
]}

Huang, Xiaotian ^{[1
]}

Zhang, Xueju ^{[1
]}

Peng, Shuying ^{[1
]}

Chen, Kai ^{[4
]}

Wang, Meining ^{[1
]}

Gong, Shouze ^{[1
]}

Zhang, Ruihan ^{[1
]}

Yin, Jinya ^{[1
]}

Li, Haiyan ^{[1
]}

Yang, Yiming ^{[1
]}

Liu, Hong ^{[1
]}

Zhang, Jiwen ^{[1
]}

Zhang, Haiyan ^{[1
]}

Zhang, Ao ^{[1
]}

Jiang, Hualiang ^{[1
]}

Luo, Cheng ^{[1
]}

Yang, Cai-Guang ^{[1
,5
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[2] Shenyang Pharmaceut Univ, Shenyang 110016, Peoples R China

[3] Peking Univ, Coll Chem & Mol Engn, Beijing 100871, Peoples R China

[4] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

[5] Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou 730000, Peoples R China

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2012年 / 134卷 / 43期

基金：

中国国家自然科学基金;

关键词：

NUCLEIC-ACID DEMETHYLASE; OBESITY-ASSOCIATED FTO; REPAIR ENZYME ALKB; OXIDATIVE DEMETHYLATION; CRYSTAL-STRUCTURES; MASS-SPECTROMETRY; ESCHERICHIA-COLI; COMMON VARIANT; ADULT OBESITY; FAT MASS;

D O I：

10.1021/ja3064149

中图分类号：

O6 [化学];

学科分类号：

070301 [无机化学];

摘要：

The direct nucleic acid repair dioxygenase FTO is an enzyme that demethylates N-6-methyladenosine (m(6)A) residues in mRNA in vitro and inside cells. FTO is the first RNA demethylase discovered that also serves a major regulatory function in mammals. Together with structure-based virtual screening and biochemical analyses, we report the first identification of several small-molecule inhibitors of human FTO demethylase. The most potent compound, the natural product rhein, which is neither a structural mimic of 2-oxoglutarate nor a chelator of metal ion, competitively binds to the FTO active site in vitro. Rhein also exhibits good inhibitory activity on m(6)A demethylation inside cells. These studies shed light on the development of powerful probes and new therapies for use in RNA biology and drug discovery.

引用

页码：17963 / 17971

页数：9

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