脱甲基酶
化学
下调和上调
基因
核糖核酸
表观遗传学
前药
单核细胞白血病
生物化学
白血病
癌症研究
生物
遗传学
作者
M.N. Prakash,Yukihiro Itoh,Yoshi Fujiwara,Yukari Takahashi,Yuri Takada,Paolo Mellini,Elghareeb E. Elboray,Mitsuhiro Terao,Yasunobu Yamashita,Chika Yamamoto,Takao Yamaguchi,Masayuki Kotoku,Yuki Kitao,Ritesh Singh,Rohini Roy,Satoshi Obika,Makoto Oba,Dan Ohtan Wang,Takayoshi Suzuki
标识
DOI:10.1021/acs.jmedchem.1c01107
摘要
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 N6-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.
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