EW-7195, a novel inhibitor of ALK5 kinase inhibits EMT and breast cancer metastasis to lung.

Abstract

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.

• Authors: Chul-Yong Park, Jee-Yeon Son, Cheng Hua Jin, Jeong-Suk Nam, Dae-Kee Kim, Yhun Yhong Sheen
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 47 Issue 17 Pg. 2642-53 (Nov 2011) ISSN: 1879-0852 [Electronic] England
• PMID: 21852112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• 3-((4-((1,2,4)triazolo(1,5-a)pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile
• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyridines
• Receptors, Transforming Growth Factor beta
• Smad2 Protein
• Triazoles
• Luciferases
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• TGFBR1 protein, human
• Tgfbr1 protein, mouse

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Transformation, Neoplastic (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Hep G2 Cells (enzymology)
• Humans
• Luciferases (metabolism)
• Lung Neoplasms (prevention & control, secondary)
• Mice
• Mice, Transgenic
• Neoplasm Invasiveness
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pyridines (therapeutic use)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• Smad2 Protein (metabolism)
• Triazoles (therapeutic use)