title: A Novel Inhibitor of the Obesity-Related Protein FTO.
abstract: Fe(II) and α-ketoglutarate-dependent fat mass and obesity associated protein (FTO)-dependent demethylation of m⁶A is important for regulation of mRNA splicing and adipogenesis. Developing FTO-specific inhibitors can help probe the biology of FTO and unravel novel therapeutic targets for treatment of obesity or obesity-associated diseases. In the present paper, we have identified that 4-chloro-6-(6'-chloro-7'-hydroxy-2',4',4'-trimethyl-chroman-2'-yl)benzene-1,3-diol (CHTB) is an inhibitor of FTO. The crystal structure of CHTB complexed with human FTO reveals that the novel small molecule binds to FTO in a specific manner. The identification of the novel small molecule offers opportunities for further development of more selective and potent FTO inhibitors.
authors.affiliation: Pathophysiology Department, Basic Medical College of Zhengzhou University , Zhengzhou 450001, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: School of Life Sciences, Tsinghua University , Beijing 100084, PR China.|Tsinghua-Peking Center for Life Sciences , Beijing 100084, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Space Biology Research and Technology Center, Engineering Research Center of Space Biology, China Academy of Space Technology , Beijing 100190, PR China.
authors.forename: Meizi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, Tsinghua University , Beijing 100084, PR China.|Tsinghua-Peking Center for Life Sciences , Beijing 100084, PR China.
authors.forename: Weijia
authors.initials: W
authors.lastname: Liu
authors.affiliation: School of Life Sciences, Tsinghua University , Beijing 100084, PR China.|Tsinghua-Peking Center for Life Sciences , Beijing 100084, PR China.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Han
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University , Zhengzhou 450001, PR China.
authors.forename: Chuanjun
authors.initials: C
authors.lastname: Song
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University , Zhengzhou 450001, PR China.
authors.forename: Wenquan
authors.initials: W
authors.lastname: Yu
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University , Zhengzhou 450001, PR China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Yang
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University , Zhengzhou 450001, PR China.
authors.forename: Ruiyong
authors.initials: R
authors.lastname: Wang
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University , Zhengzhou 450001, PR China.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Wang
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University , Zhengzhou 450001, PR China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Shi
authors.affiliation: Space Biology Research and Technology Center, Engineering Research Center of Space Biology, China Academy of Space Technology , Beijing 100190, PR China.
authors.forename: Renbin
authors.initials: R
authors.lastname: Zhao
authors.affiliation: School of Life Sciences, Tsinghua University , Beijing 100084, PR China.|Tsinghua-Peking Center for Life Sciences , Beijing 100084, PR China.
authors.forename: Jijie
authors.initials: J
authors.lastname: Chai
authors.affiliation: Pathophysiology Department, Basic Medical College of Zhengzhou University , Zhengzhou 450001, PR China.
authors.forename: Junbiao
authors.initials: J
authors.lastname: Chang
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D003460:Crystallization; D057809:HEK293 Cells; D006801:Humans; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human