EW- 7203, EW-7195, and EW-7197 inhibited Smad/TGF- signaling, cell migration, invasion, and lung metastasis of breast cancer cells in 4T1 and MDA-MB-231 orthotropic xenograft mice and MMTV/cNeu transgenic mice. drug may be needed for long-term inhibition of one signaling pathway (Connolly em et al /em ., 2012). SD-093 and SD-208, LY- 580276 (Sawyer, 2004), which act as competitive inhibitors for the ATP-binding site of TRI kinase showed anti-metastasis effect in glioma (Uhl em et al /em ., 2004) and metastatic Trimethadione mouse models (Subramanian em et al /em ., 2004; Uhl em et al /em ., 2004; Yingling em et al /em ., 2004; Mohammad em et al /em ., 2011). SD-093 and LY-580276 have been shown to block EMT and tumor cell migration in pancreatic cancer and mouse mammary epithelial cells, respectively (Subramanian em et al /em ., 2004; Peng em et al /em ., 2005). TGF-/ALK5 kinase inhibitor, LY-573636, is tested in patients with malignant melanoma, soft-tissue sarcoma, NSCLC, and ovarian cancer (Gordon em et al /em ., 2013). IN-1130, a TRI kinase inhibitor suppresses renal Rabbit polyclonal to IFNB1 fibrosis in obstructive nephropathy and metastasis from breast to lung (Moon em et al /em ., 2006). Recently, potent and highly specific TGF-/ALK5 inhibitors, EW-7203 (Park em et al /em ., 2011b), EW-7195 (Park em et al /em ., 2011a), and EW-7197 (Kim em et al /em ., 2011) were developed as orally available drugs. EW- 7203, EW-7195, and EW-7197 inhibited Smad/TGF- signaling, cell migration, invasion, and lung metastasis of breast cancer cells in 4T1 and MDA-MB-231 orthotropic xenograft mice and MMTV/cNeu transgenic mice. They inhibited epithelial to mesenchymal transition (EMT) in both TGF- treated breast cancer cells and 4T1 orthotropic xenograft mice. 1.25 mg/ Kg EW-7197 increased the survival time of 4T1-Luc and 4T1 Trimethadione breast tumor bearing mice (Kim em et al /em ., 2011). Pre-clinical study with EW-7197 was completed and ready for the clinical trial. LY2157299 (Eli-Lilly & Co) is the only TGF- receptor kinase inhibitor currently in clinical trial and a TRI kinase inhibitor that reduces growth of lung and breast cell lines (Bueno em et al /em ., 2008). LY2157299 was well tolerated at all doses from patient with Grade IV glioma. A pulmonary embolism and thrombocytopenia were two drug-related dose limiting toxicities and currently, LY2157299 is tested in four clinical trials, all of them are still recruiting patients: Phase Ib/II in stage II-IV pancreatic cancer of LY2157299 combined with gemcitabine versus gemcitabine plus placebo (“type”:”clinical-trial”,”attrs”:”text”:”NCT01373164″,”term_id”:”NCT01373164″NCT01373164); Phase II in HCC patients who have had disease progression on Sorafenib or are not eligible to receive sorafenib (“type”:”clinical-trial”,”attrs”:”text”:”NCT01246986″,”term_id”:”NCT01246986″NCT01246986); Phase Ib/IIa study combining LY2157299 with standard Temozolomide based radiochemotherapy in patients with newly diagnosed malignant glioma (“type”:”clinical-trial”,”attrs”:”text”:”NCT01220271″,”term_id”:”NCT01220271″NCT01220271); and Phase II Study ofLY2157299 mono therapy or LY2157299 plus Lomustine therapy compared to Lomustine monotherapy in patients with recurrent glioblastoma (“type”:”clinical-trial”,”attrs”:”text”:”NCT01582269″,”term_id”:”NCT01582269″NCT01582269). CONCLUSIONS TGF- pathway is being extensively evaluated as a potential therapeutic target (Yingling em et al /em ., 2004). Because of the dual role of TGF- in tumorigenesis, a comprehensive understanding of TGF- biology is required for the design successful therapeutics. It is important to discover new drugs that mimic the interactions between TGF- and its receptors and mechanistically inhibit transduction of the TGF- signaling and in turn eliminate the tumor-promoting activities of TGF-s. The TGF- inhibitors are in pre-clinical studies, and Phase I and II clinical trials. Preclinical studies have provided convincing evidence that targeting the TGF- pathway is able to inhibit Trimethadione tumor growth and metastasis em in vivo /em . And the results from clinical trial are encouraging for further new drug development. Acknowledgments This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No.20090093972)..