EW-7197, A Novel ALK-5 Kinase Inhibitor, Potently Inhibits Breast to Lung Metastasis
Menée sur des lignées cellulaires et à l'aide de xénogreffes de cancer du sein, cette étude analyse l'activité anti-métastatique d'un composé appelé EW-197, un inhibiteur de ALK5
Advanced tumors produce an excessive amount of transforming growth factor-beta (TGF-beta), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGF-beta therapeutics for cancer. We synthesized a novel small molecule TGF-beta receptor I kinase (ALK5) inhibitor termed N-[[4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl]-2-fluoroaniline (EW-7197), and we investigated its potential anti-metastatic efficacy in MMTV/c-Neu mice and 4T1 orthotopic grafted mice. EW-7197 inhibited Smad/TGF-beta signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic grafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGF-beta-treated breast cancer cells and 4T1 orthotopic grafted mice. Furthermore, EW-7197 enhanced cytotoxic T lymphocyte activity in 4T1 orthotopic grafted mice and increased the survival time of 4T1-Luc and 4T1 breast tumor-bearing mice. In summary, EW-7197 showed potent in vivo anti-metastatic activity, indicating its potential for use as an anti-cancer therapy.
http://mct.aacrjournals.org/content/early/2014/05/09/1535-7163.MCT-13-0903.abstract 2014