Identification of a new class of WNT1 inhibitor: Cancer cells migration, G-quadruplex stabilization and target validation

Lien Cheng Chang, Tsung Chih Chen, Shiag Jiun Chen, Chun Liang Chen, Chia Chung Lee, Shih Hsiung Wu, Yun Yen, Hsu Shan Huang, Jing Jer Lin

Research output: Contribution to journalArticle

Abstract

Developing the Wnt pathway inhibitors has been considered as a therapeutic approach for cancers and other Wnt-related diseases. Previously we found that the G-rich sequence of WNT1 promoter is capable of forming G-quadruplex structure and stabilizing agents for Wnt1-mediated signaling pathway. Using a established cell-based drug screen system that enabled the evaluation of WNT1 expression activity in a G-quadruplex structure dependent manner, we evaluated a series of 6-substituted 9-chloro-11H-indeno[1,2-c]quinolin-11-one derivatives that potentially inhibit the Wnt1-mediated signaling pathway. The most potent compound SJ26 showed repression of WNT1 activity in a G-quadruplex structure-dependent manner. Moreover, compound SJ26 inhibited the WNT1-mediated downstream signaling pathway and suppressed migration activity of cancer cells. Thus, we have identified a tetracyclic azafluorenone, SJ26, that is capable of binding to G-quadruplex DNA structure, repressing WNT1 expression, and inhibiting cell migration.

Original languageEnglish
Pages (from-to)67986-68001
Number of pages16
JournalOncotarget
Volume7
Issue number42
DOIs
Publication statusPublished - Oct 18 2016

Keywords

  • 6-substituted 9-chloro-11H-indeno[1,2-c]quinolin-11-ones
  • G-quadruplex
  • reporter assay
  • Wnt1-mediated signaling pathway

ASJC Scopus subject areas

  • Oncology

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