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EW-7203, a novel small molecule inhibitor of transforming growth factor-β (TGF-β) type I receptor/activin receptor-like kinase-5, blocks TGF-β1-mediated epithelial-to-mesenchymal transition in mammary epithelial cells.
Cancer Sci. 2011 Oct; 102(10):1889-96.CS

Abstract

Recently, small molecule inhibitors of transforming growth factorβ (TGF-β) type I receptor kinase ⁄ activin receptor-like kinase-5 (ALK5) have been developed to target TGF-β signalling as a therapeutic strategy for combating cancer. In the present study, the authors examined a novel small molecule inhibitor of ALK5, 3-((5- ([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)thiazol-2-ylamino)methyl)benzonitrile (EW-7203) in breast cancer cells to determine if it has potential for cancer treatment. The inhibitory effects of EW-7203 on TGF-β-induced Smad signalling 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-7203 on mammary cancer metastasis to the lung were examined using a Balb ⁄ c xenograft model system. The novel ALK5 inhibitor, EW-7203, inhibited the TGF-β1-stimulated transcriptional activation of p3TP-Lux and pCA-GA₁₂- Luc. In addition, EW-7203 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 was increased by TGF-β1. In addition, EW-7203 inhibited TGF-β1-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb ⁄ c mice, EW-7203 inhibited metastasis to the lung from breast tumors. The novel ALK5 inhibitor, EW-7203, efficiently inhibited TGF-β1-induced Smad signalling, EMT and breast tumor metastasis to the lung in vivo, demonstrating that EW-7203 has therapeutic potential for breast cancer metastasis to the lung.

Authors+Show Affiliations

College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Korea.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21707864

Citation

Park, Chul-Yong, et al. "EW-7203, a Novel Small Molecule Inhibitor of Transforming Growth Factor-β (TGF-β) Type I Receptor/activin Receptor-like Kinase-5, Blocks TGF-β1-mediated Epithelial-to-mesenchymal Transition in Mammary Epithelial Cells." Cancer Science, vol. 102, no. 10, 2011, pp. 1889-96.
Park CY, Kim DK, Sheen YY. EW-7203, a novel small molecule inhibitor of transforming growth factor-β (TGF-β) type I receptor/activin receptor-like kinase-5, blocks TGF-β1-mediated epithelial-to-mesenchymal transition in mammary epithelial cells. Cancer Sci. 2011;102(10):1889-96.
Park, C. Y., Kim, D. K., & Sheen, Y. Y. (2011). EW-7203, a novel small molecule inhibitor of transforming growth factor-β (TGF-β) type I receptor/activin receptor-like kinase-5, blocks TGF-β1-mediated epithelial-to-mesenchymal transition in mammary epithelial cells. Cancer Science, 102(10), 1889-96. https://doi.org/10.1111/j.1349-7006.2011.02014.x
Park CY, Kim DK, Sheen YY. EW-7203, a Novel Small Molecule Inhibitor of Transforming Growth Factor-β (TGF-β) Type I Receptor/activin Receptor-like Kinase-5, Blocks TGF-β1-mediated Epithelial-to-mesenchymal Transition in Mammary Epithelial Cells. Cancer Sci. 2011;102(10):1889-96. PubMed PMID: 21707864.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - EW-7203, a novel small molecule inhibitor of transforming growth factor-β (TGF-β) type I receptor/activin receptor-like kinase-5, blocks TGF-β1-mediated epithelial-to-mesenchymal transition in mammary epithelial cells. AU - Park,Chul-Yong, AU - Kim,Dae-Kee, AU - Sheen,Yhun Yhong, Y1 - 2011/07/29/ PY - 2011/6/29/entrez PY - 2011/6/29/pubmed PY - 2012/1/27/medline SP - 1889 EP - 96 JF - Cancer science JO - Cancer Sci VL - 102 IS - 10 N2 - Recently, small molecule inhibitors of transforming growth factorβ (TGF-β) type I receptor kinase ⁄ activin receptor-like kinase-5 (ALK5) have been developed to target TGF-β signalling as a therapeutic strategy for combating cancer. In the present study, the authors examined a novel small molecule inhibitor of ALK5, 3-((5- ([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)thiazol-2-ylamino)methyl)benzonitrile (EW-7203) in breast cancer cells to determine if it has potential for cancer treatment. The inhibitory effects of EW-7203 on TGF-β-induced Smad signalling 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-7203 on mammary cancer metastasis to the lung were examined using a Balb ⁄ c xenograft model system. The novel ALK5 inhibitor, EW-7203, inhibited the TGF-β1-stimulated transcriptional activation of p3TP-Lux and pCA-GA₁₂- Luc. In addition, EW-7203 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 was increased by TGF-β1. In addition, EW-7203 inhibited TGF-β1-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb ⁄ c mice, EW-7203 inhibited metastasis to the lung from breast tumors. The novel ALK5 inhibitor, EW-7203, efficiently inhibited TGF-β1-induced Smad signalling, EMT and breast tumor metastasis to the lung in vivo, demonstrating that EW-7203 has therapeutic potential for breast cancer metastasis to the lung. SN - 1349-7006 UR - https://www.unboundmedicine.com/medline/citation/21707864/EW_7203_a_novel_small_molecule_inhibitor_of_transforming_growth_factor_β__TGF_β__type_I_receptor/activin_receptor_like_kinase_5_blocks_TGF_β1_mediated_epithelial_to_mesenchymal_transition_in_mammary_epithelial_cells_ L2 - https://doi.org/10.1111/j.1349-7006.2011.02014.x DB - PRIME DP - Unbound Medicine ER -