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Cancer Cell. 2019 Apr 15;35(4):677-691.e10. doi: 10.1016/j.ccell.2019.03.006.

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

Author information

1
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.
2
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.
3
Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
4
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
5
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
6
Department of Systems Biology and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA; Key Laboratory of Hematopoietic Malignancies, Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, Zhejiang 310003, China.
7
Department of Systems Biology and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.
8
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
9
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
10
Key Laboratory of Hematopoietic Malignancies, Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, Zhejiang 310003, China.
11
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
12
University of the Chinese Academy of Sciences, Beijing 100049, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
13
University of the Chinese Academy of Sciences, Beijing 100049, China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
14
School of Life Sciences, Fudan University, Shanghai 200433, China.
15
Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. Electronic address: zhijian.qian@medicine.ufl.edu.
16
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. Electronic address: jianchen@coh.org.
17
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. Electronic address: yangcg@simm.ac.cn.

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.

KEYWORDS:

FTO inhibitor; RNA epitranscriptomics; acute myeloid leukemia; cancer therapy; structure-based design; target validation

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