FTO catalyzes the Fe(II) and 2-oxoglutarate (2OG)-dependent modification of nucleic acids, including the demethylation of N⁶-methyladenosine (m⁶A) in mRNA. FTO is a proposed target for anti-cancer therapy. Using information from crystal structures of FTO in complex with 2OG and substrate mimics, we designed and synthesized two series of FTO inhibitors, which were characterized by turnover and binding assays, and by X-ray crystallography with FTO and the related bacterial enzyme AlkB. A potent inhibitor employing binding interactions spanning the FTO 2OG and substrate binding sites was identified. Selectivity over other clinically targeted 2OG oxygenases was demonstrated, including with respect to the hypoxia-inducible factor prolyl and asparaginyl hydroxylases (PHD2 and FIH) and selected JmjC histone demethylases (KDMs). The results illustrate how structure-based design can enable the identification of potent and selective 2OG oxygenase inhibitors and will be useful for the development of FTO inhibitors for use in vivo.

中文翻译：

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选择性脂肪量和肥胖相关蛋白 (FTO) 抑制剂的基于结构的设计

FTO 催化 Fe(II) 和 2-酮戊二酸 (2OG) 依赖性核酸修饰，包括N ⁶ -甲基腺苷 (m ^{6 ) 的去甲基化}A) 在 mRNA 中。FTO 是抗癌治疗的拟议目标。利用来自与 2OG 和底物模拟物复合的 FTO 晶体结构的信息，我们设计并合成了两个系列的 FTO 抑制剂，其特征在于转换和结合测定，以及 FTO 和相关细菌酶 AlkB 的 X 射线晶体学。鉴定了采用跨越 FTO 2OG 和底物结合位点的结合相互作用的有效抑制剂。证明了对其他临床靶向 2OG 加氧酶的选择性，包​​括缺氧诱导因子脯氨酰和天冬酰胺酰羟化酶（PHD2 和 FIH）和选定的 JmjC 组蛋白去甲基化酶（KDM）。体内。