Inhibition of Breast Cancer Metastases by a Novel Inhibitor of TGFβ Receptor 1

Transforming growth factor beta (TGF beta), which is implicated in metastasis to various organs in breast cancer, is a potential target for new antitumor metastasis drugs. To identify specific inhibitors of TGF beta receptor 1 (TGF beta R1) in breast cancer metastasis, a virtual library of more than 400000 different compounds was screened by molecular docking modeling and confirmed with Smad-binding element luciferase and TGF beta R1 kinase assays. Affymetrix GeneChip expression analysis of mRNA levels and real-time polymerase chain reaction were performed to determine expression changes of TGF beta-mediated, metastasis-associated genes in breast cancer cells after treatment with the small-molecule inhibitor YR-290. YR-290 was also examined for its effects on breast cancer migration, invasion, and metastasis using transwell and epithelial-to-mesenchymal transition (EMT) assays in vitro and three different mouse (BALB/c and NU/NU nude) models (n 10 per group). KaplanMeier analyses were used to assess survival. All statistical tests were two-sided. YR-290 interacted with the kinase domain of TGF beta R1, abrogated kinase activity (half maximal inhibitory concentration 137nM, 95% confidence interval 126.4 to 147.6nM) and inhibited the TGF beta-mediated downstream signaling pathway and metastasis-associated genes in breast cancer cells. YR-290 inhibited TGF beta-modulated breast cancer cell migration and invasion. In tumor metastasis mouse models, YR-290 almost completely blocked cancer metastasis. Numbers of lung tumor nodules of mice treated with 1mg/kg and 5mg/kg YR-290 were reduced by 74.93% (95% confidence interval 61.45% to 88.41%) and 94.93% (95% confidence interval 82.13% to 100%), respectively, compared with control mice. Treatment with YR-290 also statistically significantly prolonged the survival of tumor-bearing mice. YR-290 is a novel inhibitor of tumor metastasis that works by blocking TGF beta signaling pathways.