JOURNAL ARTICLE

EW-7195, a novel inhibitor of ALK5 kinase inhibits EMT and breast cancer metastasis to lung

Chul-Yong Park, Jee-Yeon Son, Cheng Hua Jin, Jeong-Suk Nam, Dae-Kee Kim, Yhun Yhong Sheen
European Journal of Cancer 2011, 47 (17): 2642-53
21852112
Recently, researchers are actively pursuing efforts to develop potent and selective ALK5 (TβRI) kinase inhibitors for clinical development. In this study, the authors examined a novel small molecule inhibitor of ALK5, 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile (EW-7195) to determine if it has potential for cancer treatment. The inhibitory effects of EW-7195 on TGF-β-induced Smad signaling 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-7195 on mammary cancer metastasis to lung were examined using a Balb/c xenograft and MMTV/cNeu transgenic mice model system. The novel ALK5 inhibitor, EW-7195, inhibited the TGF-β(1)-stimulated transcriptional activations of p3TP-Lux and pCAGA(12)-Luc. In addition, EW-7195 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 increased by TGF-β(1). In addition, EW-7195 inhibited TGF-β(1)-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb/c and MMTV/cNeu mice, EW-7195 inhibited metastasis to lung from breast tumours. The novel ALK5 inhibitor, EW-7195, efficiently inhibited TGF-β(1)-induced Smad signaling, EMT and breast tumour metastasis to the lung in vivo, demonstrating that EW-7195 has therapeutic potential for the breast cancer metastasis to the lung.

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