Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia
Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia
复制标题
急性髓性白血病中致癌 FTO 去甲基酶的小分子靶向
DOI：
10.1016/j.ccell.2019.03.006
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发表时间：
2019-04-15
期刊：
影响因子：
50.3
通讯作者：
Yang, Cai-Guang
中科院分区：
文献类型：
--
作者：
Huang, Yue;Su, Rui;Yang, Cai-Guang
FTO是一种mRNA N-6-甲基腺苷（m（6）A）脱甲基酶，据报道可促进白血病的发生。本研究采用基于结构的合理设计方法，开发了两种有前途的FTO抑制剂FB 23和FB 23 -2，它们直接与FTO结合，选择性地抑制FTO的m（6）A脱甲基酶活性。模拟FTO耗竭，FB 23 -2在体外显著抑制人急性髓性白血病（AML）细胞系细胞和原代原始AML细胞的增殖并促进其分化/凋亡。此外，FB 23 -2显著抑制异种移植小鼠中人AML细胞系和原代细胞的进展。总的来说，我们的数据表明，FTO是一个药物靶点，小分子抑制剂靶向FTO具有治疗AML的潜力。
FTO, an mRNA N-6-methyladenosine (m(6)A) demethylase, was reported to promote leukemogenesis. Using structure-based rational design, we have developed two promising FTO inhibitors, namely FB23 and FB23-2, which directly bind to FTO and selectively inhibit FTO's m(6)A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cell line cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice. Collectively, our data suggest that FTO is a druggable target and that targeting FTO by small-molecule inhibitors holds potential to treat AML.