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

Abstract

Advanced tumors produce an excessive amount of transforming growth factor b (TGFb), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFb therapeutics for cancer. We synthesized a novel small-molecule TGFb receptor I kinase (activin receptorlike kinase 5) inhibitor termed N- [[4-([1,2,4], 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/ TGFb signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopicgrafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGFb-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 tumorbearing mice. In summary, EW-7197 showed potent in vivo antimetastatic activity, indicating its potential for use as an anticancer therapy.

TGF-β Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition

“…Because we expected EW-7197 to produce its effects via the same mechanism in LX-2 cells and BDL rats, we used a lower dose (50 nM) of EW-7197 in comparison with that used in our previous study (0.5 µM). Because EW-7197 has a relatively low IC 50 , the concentration used in this work should have resulted in 85% inhibition of ALK5 [40]. CoCl 2 is used to stabilize HIF1α, mimicking hypoxia [41].…”

Breast cancer lung metastasis: Molecular biology and therapeutic implications

“…138 Another ALK-5 inhibitor, EW-7197, also blocked breast cancer metastasis to the lung. 139 According to the results of these studies, we could presume that inhibition of TGF-b signaling alone or combined with immunotherapy may act as a promising therapy for breast cancer lung metastasis.…”

Targeting TGF-β Signaling for Therapeutic Gain

“…More recently, a first human dose (FHD) study of a new TbRI kinase SMI, TEW-7197 (MedPacto), was started as monotherapy in subjects with advanced stage solid tumors (all cancers, NCT02160106) (Jin et al 2014;Son et al 2014;Naka et al 2016). TEW-7197 has been shown to cause Smad4 degradation in cytotoxic T cells, resulting in enhanced cytotoxic T-cell activity (Yoon et al 2013), as well as reduced breast tumor metastasis to lung in mice (Son et al 2014).…”

“…So far, all published clinical studies used the TbRI SMI drug, galunisertib, whereas an additional 12 interventional trials are ongoing with this drug, and another trial uses the TbRI SMI TEW-7197 (Table 2) (Jin et al 2014;Son et al 2014;Naka et al 2016). Ongoing studies with galunisertib include its use as monotherapy with or without standard of care, such as with the alkylating agents, lomustine or temazolamide in radiochemotherapy for glioblastoma (NCT01682187, NCT01582269, NCT01220271), its use with the antimetabolite, gemcitabine, for metastatic pancreatic cancer (NCT01373164), and with or without sorafenib for hepatocellular carcinoma (NCT01246986, NCT02178358).…”