| Literature DB >> 30991027 |
Yue Huang1, Rui Su2, Yue Sheng3, Lei Dong2, Ze Dong4, Hongjiao Xu1, Tengfeng Ni4, Zijie Scott Zhang5, Tao Zhang4, Chenying Li6, Li Han7, Zhenyun Zhu8, Fulin Lian8, Jiangbo Wei5, Qiangqiang Deng9, Yungui Wang10, Mark Wunderlich11, Zhiwei Gao4, Guoyu Pan12, Dafang Zhong1, Hu Zhou13, Naixia Zhang13, Jianhua Gan14, Hualiang Jiang1, James C Mulloy11, Zhijian Qian15, Jianjun Chen16, Cai-Guang Yang17.
Abstract
FTO, an mRNA N6-methyladenosine (m6A) 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 m6A 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.Entities:
Keywords: FTO inhibitor; RNA epitranscriptomics; acute myeloid leukemia; cancer therapy; structure-based design; target validation
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Year: 2019 PMID： 30991027 PMCID： PMC6812656 DOI： 10.1016/j.ccell.2019.03.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 38.585