Data from EW-7197, a Novel ALK-5 Kinase Inhibitor, Potently Inhibits Breast to Lung Metastasis

Abstract

<div>Abstract<p>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 <i>N</i>-[[4-([1,2,4]triazolo[1,5-<i>a</i>]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1<i>H</i>-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 <i>in vivo</i> antimetastatic activity, indicating its potential for use as an anticancer therapy. <i>Mol Cancer Ther; 13(7); 1704–16. ©2014 AACR</i>.</p></div>