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Structure-Activity Relationships and Antileukemia Effects of the Tricyclic Benzoic Acid FTO Inhibitors

文献类型：期刊论文

作者Liu, Zeyu5,6; Duan, Zongliang4,6; Zhang, Deyan3,5; Xiao, Pan3; Zhang, Tao6; Xu, Hongjiao6; Wang, Chuan-Hui2; Rao, Guo-Wu2; Gan, Jianhua1; Huang, Yue3,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-07-06
页码17
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c00848
通讯作者Huang, Yue(huangyue@simm.ac.cn) ; Yang, Cai-Guang(yangcg@simm.ac.cn) ; Dong, Ze(dongze@simm.ac.cn)
英文摘要The N-6-methyladenosine (m(6)A) demethylase FTO is overexpressed in acute myeloid leukemia (AML) cells and promotes leukemogenesis. We previously developed tricyclic benzoic acid FB23 as a highly potent FTO inhibitor in vitro. However, it showed a moderate antiproliferative effect on AML cells. In this work, we performed a structure-activity relationship study of tricyclic benzoic acids as FTO inhibitors. The analog 13a exhibited excellent inhibitory effects on FTO similar to that of FB23 in vitro. In contrast to FB23, 13a exerted a strong antiproliferative effect on AML cells. Like FTO knock down, 13a upregulated ASB2 and RARA expression and increased the protein abundance while it downregulated MYC expression and decreased MYC protein abundance. These genes are key FTO targets in AML cells. Finally, 13a treatment improved the survival rate of MONOMAC6-transplanted NSG mice. Collectively, our data suggest that targeting FTO with tricyclic benzoic acid inhibitors may be a potential strategy for treating AML.
WOS关键词GENE-EXPRESSION ; RNA MODIFICATIONS ; FAT MASS ; M(6)A ; DERIVATIVES ; DEMETHYLASE ; METABOLISM
资助项目National Natural Science Foundation of China[21907101] ; National Natural Science Foundation of China[22077133] ; National Natural Science Foundation of China[21725801] ; National Natural Science Foundation of China[92153303] ; Youth Innovation Promotion Association of CAS[2020285] ; Youth Innovation Promotion Association of CAS[2021277] ; Open Research Fund of the National Center for Protein Sciences at Peking University in Beijing[KF-202101]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000831000500001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/302010]  
专题新药研究国家重点实验室
通讯作者Huang, Yue; Yang, Cai-Guang; Dong, Ze
作者单位1.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
2.Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou 310014, Peoples R China
3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Zeyu,Duan, Zongliang,Zhang, Deyan,et al. Structure-Activity Relationships and Antileukemia Effects of the Tricyclic Benzoic Acid FTO Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022:17.
APA Liu, Zeyu.,Duan, Zongliang.,Zhang, Deyan.,Xiao, Pan.,Zhang, Tao.,...&Dong, Ze.(2022).Structure-Activity Relationships and Antileukemia Effects of the Tricyclic Benzoic Acid FTO Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,17.
MLA Liu, Zeyu,et al."Structure-Activity Relationships and Antileukemia Effects of the Tricyclic Benzoic Acid FTO Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY (2022):17.

入库方式： OAI收割

来源：上海药物研究所

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