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

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Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-04-15 , 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 ₃ , Jianjun Chen ₂ , Cai-Guang Yang ₁

Affiliation

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.
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.
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.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
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.
Department of Systems Biology and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Key Laboratory of Hematopoietic Malignancies, Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, Zhejiang 310003, China.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
University of the Chinese Academy of Sciences, Beijing 100049, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
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.
School of Life Sciences, Fudan University, Shanghai 200433, China.

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.

中文翻译：

急性髓系白血病中致癌 FTO 去甲基酶的小分子靶向。

据报道，FTO 是一种 mRNA N6-甲基腺苷 (m6A) 去甲基酶，可促进白血病发生。利用基于结构的合理设计，我们开发了两种有前景的FTO抑制剂，即FB23和FB23-2，它们直接与FTO结合并选择性抑制FTO的m6A去甲基酶活性。 FB23-2 模仿 FTO 耗竭，在体外显着抑制人急性髓系白血病 (AML) 细胞系细胞和原代母细胞 AML 细胞的增殖并促进其分化/凋亡。此外，FB23-2 显着抑制异种移植小鼠中人类 AML 细胞系和原代细胞的进展。总的来说，我们的数据表明 FTO 是一个可药物靶点，并且通过小分子抑制剂靶向 FTO 具有治疗 AML 的潜力。

更新日期：2019-04-15

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