Development of Cell-Active <i>N</i><sup>6</sup>-Methyladenosine RNA Demethylase FTO Inhibitor

Baoen Chen(Chinese Academy of Sciences), Fei Ye(Chinese Academy of Sciences), Lu Yu(Shenyang Pharmaceutical University), Guifang Jia(Peking University), Xiaotian Huang(Chinese Academy of Sciences), Xueju Zhang(Chinese Academy of Sciences), Shuying Peng(Chinese Academy of Sciences), Kai Chen(University of Chicago), Meining Wang(Chinese Academy of Sciences), Shouze Gong(Chinese Academy of Sciences), Ruihan Zhang(Chinese Academy of Sciences), Jinya Yin(Chinese Academy of Sciences), Haiyan Li(Chinese Academy of Sciences), Yiming Yang(Chinese Academy of Sciences), Hong Liu(Chinese Academy of Sciences), Jiwen Zhang(Chinese Academy of Sciences), Haiyan Zhang(Chinese Academy of Sciences), Ao Zhang(Chinese Academy of Sciences), Hualiang Jiang(Chinese Academy of Sciences), Cheng Luo(Chinese Academy of Sciences), Cai‐Guang Yang(Chinese Academy of Sciences)
Journal of the American Chemical Society
October 10, 2012
10.1021/ja3064149
Cited by 446Open Access
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Abstract

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.

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