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

Abstract

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.

• Authors: Xin Fan, Huaiyu He, Jiao Li, Guoyong Luo, Yuanyuan Zheng, Jian-Kang Zhou, Juan He, Wenchen Pu, Yun Zhao
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 27 Issue 11 Pg. 2235-2244 (06 01 2019) ISSN: 1464-3391 [Electronic] England
• PMID: 31027708 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier Ltd.

Chemical References

• Antineoplastic Agents
• Benzofurans
• Enzyme Inhibitors
• Karyopherins
• MicroRNAs
• NIMA-Interacting Peptidylprolyl Isomerase
• XPO5 protein, human
• PIN1 protein, human

Topics

• Antineoplastic Agents (chemical synthesis, metabolism, pharmacology)
• Benzofurans (chemical synthesis, metabolism, pharmacology)
• Binding Sites
• Carcinoma, Hepatocellular (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, metabolism, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Karyopherins (metabolism)
• Liver Neoplasms (drug therapy)
• MicroRNAs (genetics, metabolism)
• Molecular Docking Simulation
• NIMA-Interacting Peptidylprolyl Isomerase (antagonists & inhibitors, chemistry, metabolism)
• Protein Binding
• Up-Regulation (drug effects)