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Development of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors showing potent antileukemia activities

文献类型：期刊论文

作者Zhang, Deyan1,2,3; Liu, Lu1,3; Li, Ming1,2,3; Hu, Xinyi1,2,3; Zhang, Xi1,2,3; Xia, Wenyang2,3; Wang, Zhen1,3; Song, Xiaomin1,3; Huang, Yue1,2,3; Dong, Ze1,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-05-05
卷号289页码:17
关键词RNA modification N 6-methyladenosine Demethylase FTO Structure-activity relationship Antileukemia
ISSN号0223-5234
DOI10.1016/j.ejmech.2025.117444
英文摘要Fat mass and obesity-associated protein (FTO) is the first discovered RNA N6-methyladenosine (m6A) demethylase. The highly expressed FTO protein is required to trigger oncogenic pathways in acute myeloid leukemia (AML), which makes FTO a promising antileukemia drug target. In this study, we identify 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors with good antileukemia activity. We replaced the phenyl A-ring in FB23, the first-generation of FTO inhibitor, with five-membered heterocycles and synthesized a new class of FTO inhibitors. Compound 12o/F97 shows strong enzymatic inhibitory activity and potent anti- proliferative activity. 12o/F97 selectively inhibits m6A demethylation by FTO rather than ALKBH5, and has minimal effect on m1A demethylation by ALKBH3. Additionally, 12o/F97 increases the protein levels of RARA and ASB2, while decreasing that of MYC in AML cell lines. Lastly, 12o/F97 exhibits antileukemia activity in a xenograft mice model without significant side-effects. The identification of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors not only expands the chemical space but also holds potential for anti- leukemia drug development.
WOS关键词M(6)A MODIFICATION ; RNA ; DEMETHYLASE
资助项目National Key Research and Development Program of China[2022YFC2705005] ; National Key Research and Development Program of China[2023YFD1800102] ; National Natural Science Foundation of China[92153303] ; National Natural Science Foundation of China[22077133] ; National Natural Science Foundation of China[22277127] ; Research Funds of Hangzhou Institute for Advanced Study, UCAS[2023HIAS-Y026] ; Research Funds of Hangzhou Institute for Advanced Study, UCAS[2023HIAS-V006] ; Research Funds of Hangzhou Institute for Advanced Study, UCAS[2024HIAS-Y017]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001437453500001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/316466]  
专题新药研究国家重点实验室
通讯作者Huang, Yue; Dong, Ze; Yang, Cai-Guang
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Deyan,Liu, Lu,Li, Ming,et al. Development of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors showing potent antileukemia activities[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,289:17.
APA Zhang, Deyan.,Liu, Lu.,Li, Ming.,Hu, Xinyi.,Zhang, Xi.,...&Yang, Cai-Guang.(2025).Development of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors showing potent antileukemia activities.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,289,17.
MLA Zhang, Deyan,et al."Development of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors showing potent antileukemia activities".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 289(2025):17.

入库方式： OAI收割

来源：上海药物研究所

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