State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
Department of Systems Biology and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
Cancer Cell. 2019 Apr 15;35(4):677-691.e10. doi: 10.1016/j.ccell.2019.03.006.
FTO, an mRNA N-methyladenosine (mA) 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 mA 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.
FTO 是一种 mRNA N6-甲基腺嘌呤（mA）去甲基酶，据报道可促进白血病发生。我们基于结构的合理设计开发了两种有前途的 FTO 抑制剂，即 FB23 和 FB23-2，它们可直接与 FTO 结合并选择性抑制 FTO 的 mA 去甲基酶活性。模拟 FTO 耗竭，FB23-2 可显著抑制人急性髓系白血病（AML）细胞系和原代爆发性 AML 细胞的增殖，并促进其分化/凋亡。此外，FB23-2 还可显著抑制异种移植小鼠中人类 AML 细胞系和原代细胞的进展。总的来说，我们的数据表明 FTO 是一个可成药的靶点，通过小分子抑制剂靶向 FTO 具有治疗 AML 的潜力。
