Identification of a new class of WNT1 inhibitor: Cancer cells migration, G-quadruplex stabilization and target validation.
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.
Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC.|Food and Drug Administration, Ministry of Health and Welfare, Taipei 115, Taiwan, ROC.|Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC.
Lien-Cheng
LC
Chang
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC.
Tsung-Chih
TC
Chen
School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan, ROC.
Shiag-Jiun
SJ
Chen
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC.
Chun-Liang
CL
Chen
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC.
Chia-Chung
CC
Lee
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan, ROC.
Shih-Hsiung
SH
Wu
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC.
Yun
Y
Yen
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC.|School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan, ROC.
Hsu-Shan
HS
Huang
Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC.|Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 100, Taiwan, ROC.
Jing-Jer
JJ
Lin
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005449:Fluorenes / Q000737:chemistry / Q000494:pharmacology; D054856:G-Quadruplexes; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D009690:Nucleic Acid Conformation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics; D051155:Wnt1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D005449:Fluorenes; D006576:Heterocyclic Compounds, 4 or More Rings; C000626311:SJ26 compound; D051155:Wnt1 Protein; C000613212:azafluorenone
6-substituted 9-chloro-11H-indeno[1,2-c]quinolin-11-ones; G-quadruplex; Wnt1-mediated signaling pathway; reporter assay