TY - JOUR
T1 - EW-7195, a novel inhibitor of ALK5 kinase inhibits EMT and breast cancer metastasis to lung
AU - Park, Chul Yong
AU - Son, Jee Yeon
AU - Jin, Cheng Hua
AU - Nam, Jeong Suk
AU - Kim, Dae Kee
AU - Sheen, Yhun Yhong
N1 - Funding Information:
This work was supported by the Korea Science and Engineering Foundation (KOSEF) Grant funded by the Korea government (MEST) (No. 20090093972 ).
PY - 2011/11
Y1 - 2011/11
N2 - Recently, researchers are actively pursuing efforts to develop potent and selective ALK5 (TβRI) kinase inhibitors for clinical development. In this study, the authors examined a novel small molecule inhibitor of ALK5, 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl) -1H-imidazol-2-yl)methylamino)benzonitrile (EW-7195) to determine if it has potential for cancer treatment. The inhibitory effects of EW-7195 on TGF-β-induced Smad signaling and epithelial-to-mesenchymal transition (EMT) were investigated in mammary epithelial cells using luciferase reporter assays, immunoblotting, confocal microscopy and wound healing assays. In addition, the suppressive effects of EW-7195 on mammary cancer metastasis to lung were examined using a Balb/c xenograft and MMTV/cNeu transgenic mice model system. The novel ALK5 inhibitor, EW-7195, inhibited the TGF-β 1- stimulated transcriptional activations of p3TP-Lux and pCAGA 12-Luc. In addition, EW-7195 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 increased by TGF-β 1. In addition, EW-7195 inhibited TGF-β 1-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb/c and MMTV/cNeu mice, EW-7195 inhibited metastasis to lung from breast tumours. The novel ALK5 inhibitor, EW-7195, efficiently inhibited TGF-β 1-induced Smad signaling, EMT and breast tumour metastasis to the lung in vivo, demonstrating that EW-7195 has therapeutic potential for the breast cancer metastasis to the lung.
AB - Recently, researchers are actively pursuing efforts to develop potent and selective ALK5 (TβRI) kinase inhibitors for clinical development. In this study, the authors examined a novel small molecule inhibitor of ALK5, 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl) -1H-imidazol-2-yl)methylamino)benzonitrile (EW-7195) to determine if it has potential for cancer treatment. The inhibitory effects of EW-7195 on TGF-β-induced Smad signaling and epithelial-to-mesenchymal transition (EMT) were investigated in mammary epithelial cells using luciferase reporter assays, immunoblotting, confocal microscopy and wound healing assays. In addition, the suppressive effects of EW-7195 on mammary cancer metastasis to lung were examined using a Balb/c xenograft and MMTV/cNeu transgenic mice model system. The novel ALK5 inhibitor, EW-7195, inhibited the TGF-β 1- stimulated transcriptional activations of p3TP-Lux and pCAGA 12-Luc. In addition, EW-7195 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 increased by TGF-β 1. In addition, EW-7195 inhibited TGF-β 1-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb/c and MMTV/cNeu mice, EW-7195 inhibited metastasis to lung from breast tumours. The novel ALK5 inhibitor, EW-7195, efficiently inhibited TGF-β 1-induced Smad signaling, EMT and breast tumour metastasis to the lung in vivo, demonstrating that EW-7195 has therapeutic potential for the breast cancer metastasis to the lung.
KW - ALK5 inhibitor
KW - Breast cancer
KW - Epithelial-to-mesenchymal transition
KW - Metastasis
KW - TGF-β
UR - http://www.scopus.com/inward/record.url?scp=80755163620&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2011.07.007
DO - 10.1016/j.ejca.2011.07.007
M3 - Article
C2 - 21852112
AN - SCOPUS:80755163620
VL - 47
SP - 2642
EP - 2653
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
IS - 17
ER -
