1. Academic Validation
  2. Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia

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

  • Cancer Cell. 2019 Apr 15;35(4):677-691.e10. doi: 10.1016/j.ccell.2019.03.006.
Yue Huang 1 Rui Su 2 Yue Sheng 3 Lei Dong 2 Ze Dong 4 Hongjiao Xu 1 Tengfeng Ni 4 Zijie Scott Zhang 5 Tao Zhang 4 Chenying Li 6 Li Han 7 Zhenyun Zhu 8 Fulin Lian 8 Jiangbo Wei 5 Qiangqiang Deng 9 Yungui Wang 10 Mark Wunderlich 11 Zhiwei Gao 4 Guoyu Pan 12 Dafang Zhong 1 Hu Zhou 13 Naixia Zhang 13 Jianhua Gan 14 Hualiang Jiang 1 James C Mulloy 11 Zhijian Qian 15 Jianjun Chen 16 Cai-Guang Yang 17
Affiliations

Affiliations

  • 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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