2. Academic Validation
  3. Identification of a new class of WNT1 inhibitor: Cancer cells migration, G-quadruplex stabilization and target validation

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

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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