2. Academic Validation
  3. Structure-Guided Optimization and Preclinical Evaluation of 6- O-Benzylguanine-Based Pin1 Inhibitor for Hepatocellular Carcinoma Treatment

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

  • J Med Chem. 2025 Feb 13;68(3):2869-2889. doi: 10.1021/acs.jmedchem.4c02144.
Wenchen Pu 1,  Xianyan Shen 2,  Xin Fan 1 3,  Yuanyuan Zheng 1,  Xuesha Liu 1,  Jiao Li 1,  Jian-Kang Zhou 1 4,  Juan He 1,  Rong Wei 1,  Yanqiu Gong 1,  Qingquan Zheng 1,  Yao Luo 1,  Yingli Guo 1,  Min Ai 1,  Yue Ming 1,  Zixia Ye 1,  Yun Zhao 3,  Chun Wang 2,  Yong Peng 1 5
Affiliations

Affiliations

  • 1 Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China.
  • 2 Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
  • 3 Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610041, China.
  • 4 Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China.
  • 5 Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
PMID: 39868498 DOI: 10.1021/acs.jmedchem.4c02144
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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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168872
    Pin1 Inhibitor