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Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia.
Huang, Yue; Su, Rui; Sheng, Yue; Dong, Lei; Dong, Ze; Xu, Hongjiao; Ni, Tengfeng; Zhang, Zijie Scott; Zhang, Tao; Li, Chenying; Han, Li; Zhu, Zhenyun; Lian, Fulin; Wei, Jiangbo; Deng, Qiangqiang; Wang, Yungui; Wunderlich, Mark; Gao, Zhiwei; Pan, Guoyu; Zhong, Dafang; Zhou, Hu; Zhang, Naixia; Gan, Jianhua; Jiang, Hualiang; Mulloy, James C; Qian, Zhijian; Chen, Jianjun; Yang, Cai-Guang.
Afiliação
  • Huang Y; 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.
  • Su R; 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.
  • Sheng Y; 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.
  • Dong L; 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.
  • Dong Z; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Xu H; 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.
  • Ni T; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Zhang ZS; Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
  • Zhang T; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Li C; 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.
  • Han L; Department of Systems Biology and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.
  • Zhu Z; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Lian F; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Wei J; Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
  • Deng Q; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Wang Y; Key Laboratory of Hematopoietic Malignancies, Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, Zhejiang 310003, China.
  • Wunderlich M; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • Gao Z; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Pan G; University of the Chinese Academy of Sciences, Beijing 100049, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Zhong D; 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.
  • Zhou H; 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.
  • Zhang N; 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.
  • Gan J; School of Life Sciences, Fudan University, Shanghai 200433, China.
  • Jiang H; 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.
  • Mulloy JC; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • Qian Z; 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.
  • Chen J; 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.
  • Yang CG; 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.
Cancer Cell ; 35(4): 677-691.e10, 2019 04 15.
Article em En | MEDLINE | ID: mdl-30991027
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Inibidores Enzimáticos / Dioxigenase FTO Dependente de alfa-Cetoglutarato / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2019 Tipo de documento: Article País de afiliação: China
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Inibidores Enzimáticos / Dioxigenase FTO Dependente de alfa-Cetoglutarato / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2019 Tipo de documento: Article País de afiliação: China