1. Academic Validation
  2. EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis

EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis

  • Mol Cancer Ther. 2014 Jul;13(7):1704-16. doi: 10.1158/1535-7163.MCT-13-0903.
Ji Yeon Son 1 So-Yeon Park 1 Sol-Ji Kim 1 Seon Joo Lee 1 Sang-A Park 1 Min-Jin Kim 1 Seung Won Kim 1 Dae-Kee Kim 1 Jeong-Seok Nam 2 Yhun Yhong Sheen 3
Affiliations

Affiliations

  • 1 Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and.
  • 2 Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea yysheen@ewha.ac.kr namjs@gachon.ac.kr.
  • 3 Authors' Affiliations: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul; and yysheen@ewha.ac.kr namjs@gachon.ac.kr.
Abstract

Advanced tumors produce an excessive amount of transforming growth factor β (TGFβ), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFβ therapeutics for Cancer. We synthesized a novel small-molecule TGFβ receptor I kinase (activin receptor-like kinase 5) inhibitor termed N-[[4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl]-2-fluoroaniline (EW-7197), 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/TGFβ signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGFβ-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 tumor-bearing mice. In summary, EW-7197 showed potent in vivo antimetastatic activity, indicating its potential for use as an Anticancer therapy.

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