Chemistry Research Laboratory, University of Oxford , 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
J Med Chem. 2013 May 9;56(9):3680-8. doi: 10.1021/jm400193d. Epub 2013 Apr 23.
The fat mass and obesity associated protein (FTO) is a potential target for anti-obesity medicines. FTO is a 2-oxoglutarate (2OG)-dependent N-methyl nucleic acid demethylase that acts on substrates including 3-methylthymidine, 3-methyluracil, and 6-methyladenine. To identify FTO inhibitors, we screened a set of 2OG analogues and related compounds using differential scanning fluorometry- and liquid chromatography-based assays. The results revealed sets of both cyclic and acyclic 2OG analogues that are FTO inhibitors. Identified inhibitors include small molecules that have been used in clinical studies for the inhibition of other 2OG oxygenases. Crystallographic analyses reveal inhibition by 2OG cosubstrate or primary substrate competitors as well as compounds that bind across both cosubstrate and primary substrate binding sites. The results will aid the development of more potent and selective FTO inhibitors.
肥胖相关基因（FTO）是潜在的抗肥胖药物靶点。FTO 是一种依赖 2-氧戊二酸（2OG）的 N-甲基核酸去甲基酶，可作用于包括 3-甲基胸腺嘧啶、3-甲基尿嘧啶和 6-甲基腺嘌呤在内的底物。为了鉴定 FTO 抑制剂，我们使用差示扫描荧光法和基于液相色谱的检测方法筛选了一组 2OG 类似物和相关化合物。结果显示了一系列环状和非环状 2OG 类似物都是 FTO 抑制剂。鉴定出的抑制剂包括已用于其他 2OG 加氧酶抑制的临床研究的小分子化合物。晶体学分析揭示了 2OG 辅底物或主要底物竞争抑制剂以及结合在辅底物和主要底物结合位点上的化合物的抑制作用。这些结果将有助于开发更有效和选择性的 FTO 抑制剂。
