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EW-7197Selective inhibitor of TGF-β type I receptor kinase

EW-7197

Catalog No. B5946
Size Price Stock Qty
5mg $140.00 In stock

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Sample solution is provided at 25 µL, 10mM.

Quality Control

Chemical structure

EW-7197

Protocol

Cell experiment [1,2]:

Cell lines

HaCaT (3TP-luc) and 4T1 (3TP-luc) stable cells, TGFβ-treated breast cancer cells

Preparation method

Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

96 hours

Applications

In HaCaT (3TP-luc) and 4T1 (3TP-luc) stable cells, EW-7197 potently inhibited the TGF-β1-induced luciferase reporter activity with IC50 of 16.5 and 12.1 nM, respectively. EW-7197 inhibited TGFβ-induced Smad2 or Smad3 phosphorylation and the epithelial-to-mesenchymal transition (EMT) in TGFβ-treated breast cancer cells. EW-7197 abrogated TGFβ1-induced tumor cell migration and invasion in breast cells.

Animal experiment [2]:

Animal models

Mouse mammary tumor virus (MMTV)/c-Neu mice and 4T1 orthotopic–grafted mice

Dosage form

intraperitoneal injection, 40 mg/kg, three times per week for 10 weeks

Application

EW-7197 inhibited Smad/TGFβ signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic–grafted mice. EW-7197 inhibited the epithelial-to-mesenchymal transition (EMT) in 4T1 orthotopic–grafted mice. 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.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

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.

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Chemical Properties

Cas No. 1352608-82-2 SDF Download SDF
Chemical Name N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline
Canonical SMILES CC1=NC(C2=C(N=C(N2)CNC3=CC=CC=C3F)C(C=C4)=CN5C4=NC=N5)=CC=C1
Formula C22H18FN7 M.Wt 399.42
Solubility Soluble in DMSO Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

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