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Discovery of Novel RNA Demethylase FTO Inhibitors Featuring an Acylhydrazone Scaffold with Potent Antileukemia Activity

文献类型：期刊论文

作者Liang, Xuewu4,5; Huang, Yue3,4,5; Ren, Hairu3,4,5; Liu, Qi4,5; Chen, Liang4,5; Zhao, Jiayan3; Gao, Xiangqian4,5; Lu, Jian3; Yang, Cai-Guang2,3,4,5; Liu, Hong1,3,4,5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-01-17
页码22
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c02076
英文摘要Fat mass obesity-associated protein (FTO) has been emerging as a potential therapeutic target for drug discovery in RNA epigenetics. In this work, a series of novel FTO inhibitors featuring an acylhydrazone scaffold were identified, and the optimized compounds 8t-v showed potent FTO inhibitory activities with IC50 values ranging from 7.1 to 9.4 mu M. FTO inhibitor 8t, as the lead compound, exhibited potent antiproliferative capacities against MOLM13, NB4, and THP-1 with IC50 values of 0.35, 0.59, and 0.70 mu M, respectively, and remarkably induced NB4 cell apoptosis. Compound 8t also inhibited the FTO demethylation, enhanced the abundance of m6A, stabilized FTO protein folding, and regulated the oncogenic FTO signaling pathway. Importantly, compound 8t significantly caused a tumor volume reduction and tumor weight loss with a tumor growth inhibition (TGI) value of 51% in NB4 xenograft mice. Overall, our work provided valuable lead compounds for FTO inhibitors featuring an acylhydrazone scaffold with potent antileukemia activity both in vitro and in vivo.
WOS关键词CRYSTAL-STRUCTURE ; FAT MASS ; LEUKEMIA ; M(6)A
资助项目National Natural Science Foundation of China[2023YFF1205104] ; National Key R&D Program of China[21907102] ; National Key R&D Program of China[82130105] ; National Key R&D Program of China[22337003] ; National Key R&D Program of China[92153303] ; National Key R&D Program of China[22277127] ; National Key R&D Program of China[LG202103-02-07] ; National Key R&D Program of China[LG-QS-202205-09] ; National Natural Science Foundation of China
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001399602500001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/315911]  
专题新药研究国家重点实验室
通讯作者Yang, Cai-Guang; Liu, Hong
作者单位1.Xinjiang Med Univ, Coll Pharm, Urumqi 830011, Xinjiang, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liang, Xuewu,Huang, Yue,Ren, Hairu,et al. Discovery of Novel RNA Demethylase FTO Inhibitors Featuring an Acylhydrazone Scaffold with Potent Antileukemia Activity[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025:22.
APA Liang, Xuewu.,Huang, Yue.,Ren, Hairu.,Liu, Qi.,Chen, Liang.,...&Liu, Hong.(2025).Discovery of Novel RNA Demethylase FTO Inhibitors Featuring an Acylhydrazone Scaffold with Potent Antileukemia Activity.JOURNAL OF MEDICINAL CHEMISTRY,22.
MLA Liang, Xuewu,et al."Discovery of Novel RNA Demethylase FTO Inhibitors Featuring an Acylhydrazone Scaffold with Potent Antileukemia Activity".JOURNAL OF MEDICINAL CHEMISTRY (2025):22.

入库方式： OAI收割

来源：上海药物研究所

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