Discovery of 4,6-bis(benzyloxy)-3-phenylbenzofuran as a novel Pin1 inhibitor to suppress hepatocellular carcinoma via upregulating microRNA biogenesis

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) participates in diverse cancer-associated signaling pathways, playing an oncogenic role in multiple human cancers, including hepatocellular carcinoma (HCC). Our recent works clarify that PIN1 modulates miRNAs biogenesis by interacting with ERK-phosphorylated exportin-5 (XPO5) and changing XPO5 conformation, giving a potential target for HCC treatment. Herein, we discover 4,6-bis(benzyloxy)-3-phenylbenzofuran (TAB29) as a novel PIN1 Inhibitor that targets PIN1 PPIase domain. TAB29 potently inhibits PIN1 activity with the IC₅₀ value of 874 nM and displays an excellent selectivity toward PIN1 in vitro. Cell-based biological evaluation reveals that TAB29 significantly suppresses cell proliferation of HCC cells through restoring the nucleus-to-cytoplasm export of XPO5 and upregulating mature miRNAs expression. Collectively, this work provides a promising small molecule lead compound for PIN1 inhibition, highlighting the therapeutic potential of miRNA-based treatment for human cancers.