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

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• 作者：Baoen Chen ; Fei Ye ; Lu Yu ; Guifang Jia ; Xiaotian Huang ; Xueju Zhang ; Shuying Peng ; Kai Chen ; Meining Wang ; Shouze Gong ; Ruihan Zhang ; Jinya Yin ; Haiyan Li ; Yiming Yang ; Hong Liu ; Jiwen Zhang ; Haiyan Zhang ; Ao Zhang ; Hualiang Jiang ; Cheng Luo ; Cai-Guang Yang
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：October 31, 2012
• 年：2012
• 卷：134
• 期：43
• 页码：17963-17971
• 全文大小：506K
• 年卷期：v.134,no.43(October 31, 2012)
• ISSN：1520-5126

文摘

The direct nucleic acid repair dioxygenase FTO is an enzyme that demethylates N⁶-methyladenosine (m⁶A) 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 m⁶A demethylation inside cells. These studies shed light on the development of powerful probes and new therapies for use in RNA biology and drug discovery.