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.
- 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.
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.