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

Yue Huang; Rui Su; Yue Sheng; Lei Dong; Ze Dong; Hongjiao Xu; Tengfeng Ni; Zijie Scott Zhang; Tao Zhang; Chenying Li; Li Han; Zhenyun Zhu; Fulin Lian; Jiangbo Wei; Qiangqiang Deng; Yungui Wang; Mark Wunderlich; Zhiwei Gao; Guoyu Pan; Dafang Zhong; Hu Zhou; Naixia Zhang; Jianhua Gan; Hualiang Jiang; James C Mulloy; Zhijian Qian; Jianjun Chen; Cai-Guang Yang

doi:10.1016/j.ccell.2019.03.006

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.

Authors

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

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].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alpha-Ketoglutarate-Dependent Dioxygenase FTO / antagonists & inhibitors*
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / chemistry
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Differentiation / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / enzymology
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / pathology
Methylation
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, Transgenic
Molecular Targeted Therapy
Protein Conformation
RNA, Messenger / genetics
RNA, Messenger / metabolism
Rats, Sprague-Dawley
Signal Transduction
Structure-Activity Relationship
U937 Cells
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Enzyme Inhibitors
RNA, Messenger
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
FTO protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding