Discovery of Novel Tridentate Alkenyl Diacid Derivatives as Potent ATP Citrate Lyase Inhibitors for the Treatment of Hepatocellular Carcinoma
Metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC), with enhanced <i>de novo</i> 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 <b>F28</b>, which exhibited potent ACLY inhibitory activity (IC<sub>50</sub> = 0.87 ± 0.09 μM) and favorable pharmacokinetic properties. Compound <b>F28</b> demonstrated antiproliferative activity in vitro across various cancer cell lines and attenuated lipogenesis in JHH7 and HepG2 cells. The administration of compound <b>F28</b> reduced tumor burden and liver fibrosis in a high-fat diet combined with a chemotoxic agent-induced HCC mouse model. These results position compound <b>F28</b> as a promising lead compound for the further development of ACLY inhibitors in HCC therapy.
Authors
- Jie Ma (ORCID: https://orcid.org/0000-0003-0977-8030)
- Gaolei Song
- Fajun Nan (ORCID: https://orcid.org/0000-0002-2284-3637)
- Yanfen Fang (ORCID: https://orcid.org/0000-0002-9245-4856)
- Qingbo Zhang (ORCID: https://orcid.org/0000-0001-8289-0227)
- Min Gu (ORCID: https://orcid.org/0000-0002-4518-9842)
- Jian Ding (ORCID: https://orcid.org/0000-0002-5815-4956)
- Zhifu Xie (ORCID: https://orcid.org/0009-0005-3364-0287)
- Mei Zhang (ORCID: https://orcid.org/0000-0003-0241-3020)
- Yi Chen (ORCID: https://orcid.org/0000-0002-2181-0403)
- Jingya Li (ORCID: https://orcid.org/0000-0003-3457-8153)
- Yiping Yang (ORCID: https://orcid.org/0000-0003-4426-2283)
- Yinglei Gao
- Jiaying Zhai
- Honghong Xu
- Xinyu Sun (ORCID: https://orcid.org/0009-0006-0844-2569)
- Fan Wang (ORCID: https://orcid.org/0009-0009-9261-896X)
Institutions
- Nanjing University of Chinese Medicine (CN)
- Chinese Academy of Sciences (CN)
- National Medical Products Administration (CN)
- Shanghai Institute of Materia Medica (CN)
- National Center for Drug Screening (CN)
- Advanced Research Institute (US)
- State Key Laboratory of Chemical Engineering (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00480
- Citations
- 1
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Program of Shanghai Academic Research Leader
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences