Aniline Compounds/pharmacology* ; Animals ; Breast Neoplasms/drug therapy* ; Breast Neoplasms/enzymology ; Breast Neoplasms/pathology* ; Cell Line, Tumor ; Female ; Humans ; Lung Neoplasms/enzymology ; Lung Neoplasms/prevention & control* ; Lung Neoplasms/secondary* ; Mice ; Mice, Inbred BALB C ; Protein Kinase Inhibitors/pharmacology* ; Protein-Serine-Threonine Kinases/antagonists & inhibitors* ; Random Allocation ; Receptors, Transforming Growth Factor beta/antagonists & inhibitors* ; Signal Transduction/drug effects ; Triazoles/pharmacology* ; Xenograft Model Antitumor Assays
Abstract
Advanced tumors produce an excessive amount of transforming growth factor β (TGFβ), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFβ therapeutics for cancer. We synthesized a novel small-molecule TGFβ receptor I kinase (activin receptor-like kinase 5) 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 antimetastatic efficacy in mouse mammary tumor virus (MMTV)/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 inhibited Smad/TGFβ 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 TGFβ-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 antimetastatic activity, indicating its potential for use as an anticancer therapy.