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EW-7195, a novel inhibitor of ALK5 kinase inhibits EMT and breast cancer metastasis to lung
- EW-7195, a novel inhibitor of ALK5 kinase inhibits EMT and breast cancer metastasis to lung
- Park C.-Y.; Son J.-Y.; Jin C.H.; Nam J.-S.; Kim D.-K.; Sheen Y.Y.
- Ewha Authors
- 신윤용; 김대기
- SCOPUS Author ID
- 신윤용; 김대기
- Issue Date
- Journal Title
- European Journal of Cancer
- vol. 47, no. 17, pp. 2642 - 2653
- SCI; SCIE; SCOPUS
- 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. © 2011 Elsevier Ltd. All rights reserved.
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