Qiao Yan, Zhou Bin, Zhang Meizi, Liu Weijia, Han Zhifu, Song Chuanjun, Yu Wenquan, Yang Qinghua, Wang Ruiyong, Wang Shaomin, Shi Shuai, Zhao Renbin, Chai Jijie, Chang Junbiao
Pathophysiology Department, Basic Medical College of Zhengzhou University , Zhengzhou 450001, PR China.
School of Life Sciences, Tsinghua University , Beijing 100084, PR China.
Biochemistry. 2016 Mar 15;55(10):1516-22. doi: 10.1021/acs.biochem.6b00023. Epub 2016 Mar 4.
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.
亚铁离子（Fe(II)）和α-酮戊二酸依赖性的脂肪量与肥胖相关蛋白（FTO）介导的N6-甲基腺苷（m⁶A）去甲基化对于mRNA剪接和脂肪生成的调控至关重要。开发FTO特异性抑制剂有助于探究FTO的生物学特性，并揭示治疗肥胖症或肥胖相关疾病的新治疗靶点。在本文中，我们已确定4-氯-6-(6'-氯-7'-羟基-2',4',4'-三甲基-色满-2'-基)苯-1,3-二醇（CHTB）是FTO的一种抑制剂。CHTB与人FTO复合的晶体结构表明，这种新型小分子以特定方式与FTO结合。这种新型小分子的鉴定为进一步开发更具选择性和强效的FTO抑制剂提供了机会。
