College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea.
Eur J Cancer. 2011 Nov;47(17):2642-53. doi: 10.1016/j.ejca.2011.07.007. Epub 2011 Aug 16.
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.
最近，研究人员积极努力开发用于临床开发的有效且选择性的 ALK5（TβRI）激酶抑制剂。在这项研究中，作者研究了一种新型的 ALK5 小分子抑制剂，3-((4-([1,2,4]三唑并[1,5-a]吡啶-6-基)-5-(6-甲基吡啶-2-基)-1H-咪唑-2-基)甲氨基)苯甲腈（EW-7195），以确定其是否具有治疗癌症的潜力。使用荧光素酶报告基因分析、免疫印迹、共聚焦显微镜和划痕愈合分析，在乳腺上皮细胞中研究了 EW-7195 对 TGF-β 诱导的 Smad 信号转导和上皮间质转化（EMT）的抑制作用。此外，使用 Balb/c 异种移植和 MMTV/cNeu 转基因小鼠模型系统研究了 EW-7195 对乳腺癌细胞向肺部转移的抑制作用。新型 ALK5 抑制剂 EW-7195 抑制 TGF-β(1)刺激的 p3TP-Lux 和 pCAGA(12)-Luc 的转录激活。此外，EW-7195 降低了磷酸化 Smad2 水平和 TGF-β(1)诱导的 Smad2 核转位。此外，EW-7195 抑制了 TGF-β(1)诱导的 NMuMG 细胞 EMT 和伤口愈合。此外，在异种移植的 Balb/c 和 MMTV/cNeu 小鼠中，EW-7195 抑制了乳腺癌向肺部的转移。新型 ALK5 抑制剂 EW-7195 有效抑制 TGF-β(1)诱导的 Smad 信号转导、EMT 和乳腺癌向肺部的转移，表明 EW-7195 具有治疗乳腺癌向肺部转移的潜力。
