Structure-Guided Optimization and Preclinical Evaluation of 6-O-Benzylguanine-Based Pin1 Inhibitor for Hepatocellular Carcinoma Treatment

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-01-27 DOI:10.1021/acs.jmedchem.4c02144

Wenchen Pu, Xianyan Shen, Xin Fan, Yuanyuan Zheng, Xuesha Liu, Jiao Li, Jian-Kang Zhou, Juan He, Rong Wei, Yanqiu Gong, Qingquan Zheng, Yao Luo, Yingli Guo, Min Ai, Yue Ming, Zixia Ye, Yun Zhao, Chun Wang, Yong Peng

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Abstract

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 API-1 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 API-1 motivated us to find improved Pin1 inhibitors. Herein, we designed and synthesized diverse 6-O-benzylguanine derivatives and discovered API-32 as a novel Pin1 inhibitor with better stability and pharmacokinetic property over API-1. API-32 directly interacted with the Pin1 PPIase domain to inhibit Pin1 activity. API-32 significantly suppressed the cell proliferation and migration of HCC cells by blocking Pin1’s downstream signal. Moreover, API-32 exhibited an enhanced inhibitory function against the HCC tumor in mice models without obvious toxicity, making it a promising drug candidate for HCC treatment.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.