Discovery of 4, 6-bis(benzyloxy)-3-phenylbenzofuran as a novel Pin1 inhibitor to suppress hepatocellular carcinoma via upregulating microRNA biogenesis. Issue 11 (1st June 2019)

• Record Type: Journal Article
• Authors: Fan, Xin; He, Huaiyu; Li, Jiao; Luo, Guoyong; Zheng, Yuanyuan; Zhou, Jian-Kang; He, Juan; Pu, Wenchen; Zhao, Yun
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 11(2019)
• Page Start: 2235
• Page End: 2244
• Publication Date: 2019-06-01
• Subjects: Pin1 -- Hepatocellular carcinoma -- microRNA -- Benzofuran -- XPO5; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.04.028
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 thatTAB29 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.