Identification of Potent and Selective Inhibitors of Fat Mass Obesity-Associated Protein Using a Fragment-Merging Approach
Identification of Potent and Selective Inhibitors of Fat Mass Obesity-Associated Protein Using a Fragment-Merging Approach
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DOI：
10.1021/acs.jmedchem.1c01107
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发表时间：
2021-11-03
影响因子：
7.3
通讯作者：
Suzuki, Takayoshi
中科院分区：
文献类型：
--
作者：
Prakash, Muthuraj;Itoh, Yukihiro;Suzuki, Takayoshi
脂肪量肥胖相关蛋白（FTO）是一种DNA/RNA脱甲基酶，参与多种基因的表观遗传调控，被认为是肥胖、癌症和神经系统疾病的治疗靶点。在这里，我们的目的是通过合并先前报道的FTO抑制剂的片段来设计新的FTO选择性抑制剂。在合成的类似物中，化合物11b合并了Hz（3）和MA（4）的关键片段，相对于烷基化修复同源物5（ALKBH 5）（另一种DNA/RNA去甲基化酶）选择性地抑制FTO。用11b的前药处理急性单核细胞白血病NOMO-1细胞降低了急性单核细胞白血病细胞的活力，增加了mRNA中FTO底物N-6-甲基腺苷的水平，并诱导了FTO靶基因MYC的上调和RARA的下调。因此，Hz（3）/MA（4）杂合类似物代表进入一类新的FTO选择性抑制剂。
Fat mass obesity-associated protein (FTO) is a DNA/RNA demethylase involved in the epigenetic regulation of various genes and is considered a therapeutic target for obesity, cancer, and neurological disorders. Here, we aimed to design novel FTO-selective inhibitors by merging fragments of previously reported FTO inhibitors. Among the synthesized analogues, compound 11b, which merges key fragments of Hz (3) and MA (4), inhibited FTO selectively over alkylation repair homologue 5 (ALKBH5), another DNA/RNA demethylase. Treatment of acute monocytic leukemia NOMO-1 cells with a prodrug of 11b decreased the viability of acute monocytic leukemia cells, increased the level of the FTO substrate N-6-methyladenosine in mRNA, and induced upregulation of MYC and downregulation of RARA, which are FTO target genes. Thus, Hz (3)/MA (4) hybrid analogues represent an entry into a new class of FTO-selective inhibitors.