title: Development of cell-active N6-methyladenosine RNA demethylase FTO inhibitor.
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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Baoen
authors.initials: B
authors.lastname: Chen
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Lu
authors.initials: L
authors.lastname: Yu
authors.forename: Guifang
authors.initials: G
authors.lastname: Jia
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Huang
authors.forename: Xueju
authors.initials: X
authors.lastname: Zhang
authors.forename: Shuying
authors.initials: S
authors.lastname: Peng
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Meining
authors.initials: M
authors.lastname: Wang
authors.forename: Shouze
authors.initials: S
authors.lastname: Gong
authors.forename: Ruihan
authors.initials: R
authors.lastname: Zhang
authors.forename: Jinya
authors.initials: J
authors.lastname: Yin
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.forename: Yiming
authors.initials: Y
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Jiwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Cai-Guang
authors.initials: CG
authors.lastname: Yang
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000880:Anthraquinones; D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; C020491:rhein