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EW-7197

现货
Catalog No.
B5946
TGF-β I型受体激酶抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 1,400.00
现货

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Background

Description:

IC50: 0.013 μM

Transforming growth factor-β (TGF-β) belongs to the TGF-β superfamily, which consists of TGF-β1, TGF-β2, TGF-β3. TGF-β and its receptors are often chronically overexpressed in various human diseases, such as cancer, tissue fibrosis, inflammation, and autoimmunity. Therefore, blockade of TGF-β signaling pathway is an attractive target for drug development. Following TGF-β binding to the constitutively active type II receptor, the type I receptor (ALK5) is phosphorylated and creates a binding site for Smad2/Smad3 proteins, which are further phosphorylated. EW-7197 is a highly potent, selective inhibitor of TGF-β type I receptor kinase.

In vitro: EW-7197 inhibited ALK5 with IC50 value of 0.013 μM in a kinase assay and with IC50 values of 0.0165 and 0.0121 μM in HaCaT stable cells and 4T1 stable cells, respectively, in a luciferase assay. Selectivity profiling of EW-7197 using a panel of protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor [1].

In vivo: EW-7197 inhibited Smad/TGF-βsignaling, invasion, cell migration, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic–grafted mice. EW-7197 inhibited the epithelial-to-mesenchymal transition in both TGF-β-treated breast cancer cells and 4T1 orthotopic–grafted mice as well[2].

Clinical trial: The First in human dose escalation study of EW-7197 in subjects with advanced stage solid tumors is ongoing [3].

Reference:
[1] Jin CH, Krishnaiah M, Sreenu D, Subrahmanyam VB, Rao KS, Lee HJ, Park SJ, Park HJ, Lee K, Sheen YY, Kim DK.  Discovery of 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): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent. J Med Chem. 2014 May 22;57(10):4213-38.
[2] Son JY, Park SY, Kim SJ, Lee SJ, Park SA, Kim MJ, Kim SW, Kim DK, Nam JS, Sheen YY.  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. Epub 2014 May 9.
[3] https://clinicaltrials. gov/ct2/show/NCT02160106?term=EW-7197&rank=1

文献引用

1. Wei HJ, Pareek TK, et al. "A unique tolerizing dendritic cell phenotype induced by the synthetic triterpenoid CDDO-DFPA (RTA-408) is protective against EAE." Sci Rep. 2017 Aug 29;7(1):9886. PMID:28851867

Chemical Properties

StorageStore at -20°C
M.Wt399.42
Cas No.1352608-82-2
FormulaC22H18FN7
Solubility≥39.9mg/mL in DMSO
Chemical NameN-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline
SDFDownload SDF
Canonical SMILESCC1=NC(C2=C(N=C(N2)CNC3=CC=CC=C3F)C(C=C4)=CN5C4=NC=N5)=CC=C1
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验 [1,2]:

细胞系

TGF-β处理的乳腺癌细胞,HaCaT (3TP-luc)和4T1 (3TP-luc)细胞

溶解方法

可溶于DMSO。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

96小时

应用

在HaCaT(3TP-luc)和4T1(3TP-luc)细胞中,EW-7197有效抑制TGF-β1诱导的荧光素酶报告基因活性,IC50分别为16.5和12.1 nM。在TGF-β处理的乳腺癌细胞中,EW-7197抑制TGF-β诱导的Smad2或Smad3磷酸化和上皮-间质转化(EMT)。在乳腺细胞中,EW-7197消除了TGFβ1诱导的肿瘤细胞迁移和侵袭。

动物实验 [2]:

动物模型

小鼠乳腺肿瘤病毒(MMTV)/c-Neu小鼠和4T1原位移植小鼠

给药剂量

腹腔注射,40 mg/kg,每周三次,持续10周

应用

在MMTV/c-Neu小鼠和4T1原位移植小鼠中,EW-7197抑制Smad/TGFβ信号传导、细胞迁移、侵袭和肺转移。在4T1原位移植小鼠中,EW-7197抑制上皮-间质转化(EMT)。在4T1原位移植小鼠中,EW-7197增强细胞毒性T淋巴细胞活性,增加4T1-Luc和4T1乳腺肿瘤小鼠的存活时间。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Son J Y, Park S Y, Kim S J, et al. EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis[J]. Molecular cancer therapeutics, 2014, 13(7): 1704-1716.

[2]. Jin C H, Krishnaiah M, Sreenu D, et al. Discovery of N-((4-([1, 2, 4] Triazolo [1, 5-a] pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1 H-imidazol-2-yl) methyl)-2-fluoroaniline (EW-7197): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of TGF-β Type I Receptor Kinase as Cancer Immunotherapeutic/Antifibrotic Agent[J]. Journal of medicinal chemistry, 2014, 57(10): 4213-4238.

质量控制

化学结构

EW-7197