Structure-Guided Optimization and Preclinical Evaluation of 6-<i>O</i>-Benzylguanine-Based Pin1 Inhibitor for Hepatocellular Carcinoma Treatment
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths globally, and the need for effective systemic therapies for HCC is urgent. Our previous work reveals that Pin1 is a potential anti-HCC target, which regulates miRNA biogenesis and identifies <b>API-1</b> as a novel Pin1 inhibitor to suppresses HCC. However, a great demand in HCC therapy as well as the limited chemical stability and pharmacokinetic feature of <b>API-1</b> motivated us to find improved Pin1 inhibitors. Herein, we designed and synthesized diverse 6-<i>O</i>-benzylguanine derivatives and discovered <b>API-32</b> as a novel Pin1 inhibitor with better stability and pharmacokinetic property over <b>API-1</b>. <b>API-32</b> directly interacted with the Pin1 PPIase domain to inhibit Pin1 activity. <b>API-32</b> significantly suppressed the cell proliferation and migration of HCC cells by blocking Pin1's downstream signal. Moreover, <b>API-32</b> exhibited an enhanced inhibitory function against the HCC tumor in mice models without obvious toxicity, making it a promising drug candidate for HCC treatment.
Authors
- Yingli Guo (ORCID: https://orcid.org/0000-0003-4117-6865)
- Jiankang Zhou (ORCID: https://orcid.org/0000-0002-9147-3043)
- Wenchen Pu (ORCID: https://orcid.org/0000-0003-0929-9566)
- Min Ai (ORCID: https://orcid.org/0000-0002-7753-3310)
- Qingquan Zheng
- Xianyan Shen
- Yanqiu Gong (ORCID: https://orcid.org/0000-0001-7890-5158)
- Xuesha Liu
- Xin Fan (ORCID: https://orcid.org/0000-0003-4745-0837)
- Zixia Ye
- Yun Fu Zhao (ORCID: https://orcid.org/0000-0002-6357-9422)
- Yuanyuan Zheng (ORCID: https://orcid.org/0000-0002-7595-1375)
- Yong Peng (ORCID: https://orcid.org/0000-0002-1181-3467)
- Chun Wang (ORCID: https://orcid.org/0000-0001-8553-1182)
- Jiao Li (ORCID: https://orcid.org/0009-0004-7706-6224)
- Wei Rong (ORCID: https://orcid.org/0000-0002-7897-576X)
- Yao Luo (ORCID: https://orcid.org/0000-0002-4542-3504)
- Yue Ming (ORCID: https://orcid.org/0000-0002-4719-0759)
- Juan He (ORCID: https://orcid.org/0000-0003-0199-3852)
Institutions
- Chinese Academy of Sciences (CN)
- Chengdu Medical College (CN)
- Sichuan University (CN)
- Frontier Medical College (PK)
- Research Institute of General Pathology and Pathophysiology, the Russian Academy of Medical Sciences (RU)
- Center for Molecular Medicine and Immunology (US)
- Chengdu Institute of Biology (CN)
- State Key Laboratory of Biotherapy
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-01-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02144
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Department of Science and Technology of Sichuan Province
- National Key Research and Development Program of China
- West China Hospital, Sichuan University