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

  • Oncotarget. 2016 Oct 18;7(42):67986-68001. doi: 10.18632/oncotarget.6622.
Lien-Cheng Chang  1  2  3 ,  Tsung-Chih Chen  3 ,  Shiag-Jiun Chen  4 ,  Chun-Liang Chen  3 ,  Chia-Chung Lee  3 ,  Shih-Hsiung Wu  5 ,  Yun Yen  3 ,  Hsu-Shan Huang  3  4 ,  Jing-Jer Lin  1  6
Affiliations
  • 1. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC.
  • 2. Food and Drug Administration, Ministry of Health and Welfare, Taipei 115, Taiwan, ROC.
  • 3. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC.
  • 4. School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan, ROC.
  • 5. Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan, ROC.
  • 6. Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 100, Taiwan, ROC.
PMID: 27626678 DOI: 10.18632/oncotarget.6622
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.

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