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Discovery of Novel Tridentate Alkenyl Diacid Derivatives as Potent ATP Citrate Lyase Inhibitors for the Treatment of Hepatocellular Carcinoma

文献类型：期刊论文

作者Yang, Yurou3,6; Zhai, Jimao3,5; Wang, Fan1; Song, Gaolei6; Xu, Honghong6; Sun, Xinyu6; Zhang, Qingbo3,6; Ma, Jie6; Gu, Min6; Gao, Yinglei5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-08-14
卷号68期号:15页码:15598-15616
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c00480
通讯作者Xie, Zhifu(zfxie@simm.ac.cn) ; Fang, Yanfen(yffang@simm.ac.cn) ; Nan, Fajun(fjnan@simm.ac.cn)
英文摘要Metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC), with enhanced de novo lipogenesis playing a critical role in tumor progression. ATP citrate lyase (ACLY), linking carbohydrate metabolism to lipid biosynthesis, has emerged as a promising therapeutic target in HCC. Herein, we report the development of a series of novel tridentate alkenyl diacid derivatives as potent ACLY inhibitors. Guided by molecular docking and structure-activity relationship studies, we identified compound F28, which exhibited potent ACLY inhibitory activity (IC50 = 0.87 +/- 0.09 mu M) and favorable pharmacokinetic properties. Compound F28 demonstrated antiproliferative activity in vitro across various cancer cell lines and attenuated lipogenesis in JHH7 and HepG2 cells. The administration of compound F28 reduced tumor burden and liver fibrosis in a high-fat diet combined with a chemotoxic agent-induced HCC mouse model. These results position compound F28 as a promising lead compound for the further development of ACLY inhibitors in HCC therapy.
WOS关键词CANCER
资助项目Program of Shanghai Academic Research Leader[2023ZD0507800] ; Noncommunicable Chronic Diseases-National Science and Technology Major Project[22XD1404400] ; Program of Shanghai Academic Research Leader[SIMM0120231001] ; Project of Shanghai Institute of Materia Medica, Chinese Academy of Sciences
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001530815300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/318846]  
专题中国科学院上海药物研究所
通讯作者Xie, Zhifu; Fang, Yanfen; Nan, Fajun
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Yurou,Zhai, Jimao,Wang, Fan,et al. Discovery of Novel Tridentate Alkenyl Diacid Derivatives as Potent ATP Citrate Lyase Inhibitors for the Treatment of Hepatocellular Carcinoma[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(15):15598-15616.
APA Yang, Yurou.,Zhai, Jimao.,Wang, Fan.,Song, Gaolei.,Xu, Honghong.,...&Nan, Fajun.(2025).Discovery of Novel Tridentate Alkenyl Diacid Derivatives as Potent ATP Citrate Lyase Inhibitors for the Treatment of Hepatocellular Carcinoma.JOURNAL OF MEDICINAL CHEMISTRY,68(15),15598-15616.
MLA Yang, Yurou,et al."Discovery of Novel Tridentate Alkenyl Diacid Derivatives as Potent ATP Citrate Lyase Inhibitors for the Treatment of Hepatocellular Carcinoma".JOURNAL OF MEDICINAL CHEMISTRY 68.15(2025):15598-15616.

入库方式： OAI收割

来源：上海药物研究所

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