The peptidyl-prolyl isomerase Pin1 is correlated with the progression of cervical cancer via regulating numerous oncogenic and tumor suppressor pathways. p65 is a crucial regulator of tumorigenesis that is regulated by Pin1, and p65 signaling suppression can enhance the antitumor efficacy of doxorubicin (DOX). Here, we utilized a structural mimicry approach to synthesize a series of dibenzothiophene analogues and evaluated their ability to inhibit Pin1 activity. Compound 1a was identified as a potent Pin1 inhibitor that inhibited p65 signaling in vitro and in cervical cancer cells. Moreover, compound 1a enhanced the cytotoxicity of DOX in cervical cancer cells via reducing p65 nuclear accumulation and enhancing DOX uptake. These compounds are promising scaffolds for developing more potent Pin1 inhibitors against cervical cancer, either alone or in combination with anticancer drugs such as DOX.
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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