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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 30991027 DOI: 10.1016/j.ccell.2019.03.006
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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