EW‐7203, a novel small molecule inhibitor of transforming growth factor‐β (TGF‐β) type I receptor/activin receptor‐like kinase‐5, blocks TGF‐β1‐mediated epithelial‐to‐mesenchymal transition in mammary epithelial cells

摘要

AbstractRecently, small molecule inhibitors of transforming growth factor-β (TGF-β) type I receptor kinase/activin receptor-like kinase-5 (ALK5) have been developed to target TGF-β 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-β-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-β1-stimulated transcriptional activation of p3TP-Lux and pCAGA₁₂-Luc. In addition, EW-7203 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 was increased by TGF-β1. In addition, EW-7203 inhibited TGF-β1-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-β1-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)