Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia

被引：814

作者：

Huang, Yue ^{[1
,2
]}

Su, Rui ^{[3
,4
,5
]}

Sheng, Yue ^{[6
,7
]}

Dong, Lei ^{[3
,4
,5
]}

Dong, Ze ^{[1
]}

Xu, Hongjiao ^{[1
,2
]}

Ni, Tengfeng ^{[1
]}

Zhang, Zijie Scott ^{[8
,9
]}

Zhang, Tao ^{[1
]}

Li, Chenying ^{[3
,4
,10
]}

Han, Li ^{[3
,4
]}

Zhu, Zhenyun ^{[11
]}

Lian, Fulin ^{[11
]}

Wei, Jiangbo ^{[8
,9
]}

Deng, Qiangqiang ^{[12
]}

Wang, Yungui ^{[10
]}

Wunderlich, Mark ^{[13
]}

Gao, Zhiwei ^{[1
]}

Pan, Guoyu ^{[2
,12
]}

Zhong, Dafang ^{[1
,2
]}

Zhou, Hu ^{[2
,11
]}

Zhang, Naixia ^{[2
,11
]}

Gan, Jianhua ^{[14
]}

Jiang, Hualiang ^{[1
,2
]}

Mulloy, James C. ^{[13
]}

Qian, Zhijian ^{[6
,7
]}

Chen, Jianjun ^{[3
,4
,5
]}

Yang, Cai-Guang ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[2] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[3] City Hope Natl Med Ctr, Dept Syst Biol, Duarte, CA 91010 USA

[4] City Hope Natl Med Ctr, Gehr Family Ctr Leukemia Res, Duarte, CA 91010 USA

[5] Univ Cincinnati, Coll Med, Dept Canc Biol, Cincinnati, OH 45219 USA

[6] Univ Florida, Dept Med, Hlth Canc Ctr, Gainesville, FL 32610 USA

[7] Univ Illinois, Dept Med, Chicago, IL 60612 USA

[8] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

[9] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA

[10] Zhejiang Univ, Key Lab Hematopoiet Malignancies, Dept Hematol, Affiliated Hosp 1, Hangzhou 310003, Zhejiang, Peoples R China

[11] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

[12] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[13] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[14] Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China

来源：

CANCER CELL | 2019年 / 35卷 / 04期

基金：

中国博士后科学基金; 中国国家自然科学基金; 国家重点研发计划;

关键词：

MESSENGER-RNA; FAT MASS; M(6)A; METHYLATION; N-6-METHYLADENOSINE; PROTEIN; BINDING; TRANSLATION; CELLS; DNA;

D O I：

10.1016/j.ccell.2019.03.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：677 / +

页数：25

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