Journal
CANCER SCIENCE
Volume 102, Issue 10, Pages 1889-1896Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1349-7006.2011.02014.x
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Funding
- Korea Science and Engineering Foundation (KOSEF)
- Korea government (MEST) [20090093972]
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Recently, small molecule inhibitors of transforming growth factor-beta (TGF-beta) type I receptor kinase/activin receptor-like kinase-5 (ALK5) have been developed to target TGF-beta signalling as a therapeutic strategy for combating cancer. In the present study, the authors examined a novel small molecule inhibitor of ALK5, 3-((5-([1,2,4] triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)thiazol-2-ylamino)methyl) benzonitrile (EW-7203) in breast cancer cells to determine if it has potential for cancer treatment. The inhibitory effects of EW-7203 on TGF-beta-induced Smad signalling and epithelial-to-mesenchymal transition (EMT) were investigated in mammary epithelial cells using luciferase reporter assays, immunoblotting, confocal microscopy and wound healing assays. In addition, the suppressive effects of EW-7203 on mammary cancer metastasis to the lung were examined using a Balb/c xenograft model system. The novel ALK5 inhibitor, EW-7203, inhibited the TGF-beta 1-stimulated transcriptional activation of p3TP-Lux and pCA-GA(12)-Luc. In addition, EW-7203 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 was increased by TGF-beta 1. In addition, EW-7203 inhibited TGF-beta 1-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb/c mice, EW-7203 inhibited metastasis to the lung from breast tumors. The novel ALK5 inhibitor, EW-7203, efficiently inhibited TGF-beta 1-induced Smad signalling, EMT and breast tumor metastasis to the lung in vivo, demonstrating that EW-7203 has therapeutic potential for breast cancer metastasis to the lung. (Cancer Sci 2011; 102: 1889-1896)
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