EW-7197Selective inhibitor of TGF-β type I receptor kinase CAS# 1352608-82-2 |
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Quality Control & MSDS
3D structure
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| Cas No. | 1352608-82-2 | SDF | Download SDF |
| PubChem ID | 54766013 | Appearance | Powder |
| Formula | C22H18FN7 | M.Wt | 399.42 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | Vactosertib | ||
| Solubility | DMSO : ≥ 83.3 mg/mL (208.55 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 2-fluoro-N-[[5-(6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-imidazol-2-yl]methyl]aniline | ||
| SMILES | CC1=CC=CC(=N1)C2=C(N=C(N2)CNC3=CC=CC=C3F)C4=CN5C(=NC=N5)C=C4 | ||
| Standard InChIKey | FJCDSQATIJKQKA-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C22H18FN7/c1-14-5-4-8-18(27-14)22-21(15-9-10-20-25-13-26-30(20)12-15)28-19(29-22)11-24-17-7-3-2-6-16(17)23/h2-10,12-13,24H,11H2,1H3,(H,28,29) | ||
| 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. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | EW-7197 is a highly potent, selective, and orally bioavailable TGF-β receptor ALK4/ALK5 inhibitor with IC50 of 13 nM and 11 nM, respectively.
target: ALK4/ALK5
IC 50: 13 nM for TGF-β receptor ALK4, 11 nM for TGF-β receptor ALK5. [1]
In vitro: EW-7197 inhibits TGFβ-induced Smad2 or Smad3 phosphorylation and the epithelial-to-mesenchymal transition (EMT) in TGFβ-treated breast cancer cells. In addition, EW-7197 also abrogates TGFβ1-induced tumor cell migration and invasion in breast cells. EW-7197 inhibited Smad/TGFβ signaling, cell migration, invasion, and lung metastasis in mouse mammary tumor virus. [2]
In vivo: EW-7197 inhibition downregulates Smad4 in melanoma-bearing mice. EW-7197 induces ubiquitin-mediated degradation of Smad4 in melanoma-bearing mice. In a mouse B16 melanoma model, EW-7197 (2.5 mg/kg daily p.o.) suppresses the progression of melanoma with enhanced cytotoxic T-lymphocyte (CTL) responses. EW-7197 dissolved in artificial gastric fluid formulation (vehicle; ddH2O 900 ml, conc. HCl 7 ml, NaCl 2.0 g, pepsin 3.2 g) was given orally by feeding needle to mice from 4 days after inoculation. [3] References: | |||||
EW-7197 Dilution Calculator
EW-7197 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.5036 mL | 12.5182 mL | 25.0363 mL | 50.0726 mL | 62.5908 mL |
| 5 mM | 0.5007 mL | 2.5036 mL | 5.0073 mL | 10.0145 mL | 12.5182 mL |
| 10 mM | 0.2504 mL | 1.2518 mL | 2.5036 mL | 5.0073 mL | 6.2591 mL |
| 50 mM | 0.0501 mL | 0.2504 mL | 0.5007 mL | 1.0015 mL | 1.2518 mL |
| 100 mM | 0.025 mL | 0.1252 mL | 0.2504 mL | 0.5007 mL | 0.6259 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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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
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EW-7197 inhibits hepatic, renal, and pulmonary fibrosis by blocking TGF-beta/Smad and ROS signaling.[Pubmed:25487606]
Cell Mol Life Sci. 2015 May;72(10):2023-39.
Fibrosis is an inherent response to chronic damage upon immense apoptosis or necrosis. Transforming growth factor-beta1 (TGF-beta1) signaling plays a key role in the fibrotic response to chronic liver injury. To develop anti-fibrotic therapeutics, we synthesized a novel small-molecule inhibitor of the TGF-beta type I receptor kinase (ALK5), EW-7197, and evaluated its therapeutic potential in carbon tetrachloride (CCl4) mouse, bile duct ligation (BDL) rat, bleomycin (BLM) mouse, and unilateral ureteral obstruction (UUO) mouse models. Western blot, immunofluorescence, siRNA, and ChIP analysis were carried out to characterize EW-7197 as a TGF-beta/Smad signaling inhibitor in LX-2, Hepa1c1c7, NRK52E, and MRC5 cells. In vivo anti-fibrotic activities of EW-7197 were examined by microarray, immunohistochemistry, western blotting, and a survival study in the animal models. EW-7197 decreased the expression of collagen, alpha-smooth muscle actin (alpha-SMA), fibronectin, 4-hydroxy-2, 3-nonenal, and integrins in the livers of CCl4 mice and BDL rats, in the lungs of BLM mice, and in the kidneys of UUO mice. Furthermore, EW-7197 extended the lifespan of CCl4 mice, BDL rats, and BLM mice. EW-7197 blocked the TGF-beta1-stimulated production of reactive oxygen species (ROS), collagen, and alpha-SMA in LX-2 cells and hepatic stellate cells (HSCs) isolated from mice. Moreover, EW-7197 attenuated TGF-beta- and ROS-induced HSCs activation to myofibroblasts as well as extracellular matrix accumulation. The mechanism of EW-7197 appeared to be blockade of both TGF-beta1/Smad2/3 and ROS signaling to exert an anti-fibrotic activity. This study shows that EW-7197 has a strong potential as an anti-fibrosis therapeutic agent via inhibition of TGF-beta-/Smad2/3 and ROS signaling.
Novel oral transforming growth factor-beta signaling inhibitor EW-7197 eradicates CML-initiating cells.[Pubmed:26583567]
Cancer Sci. 2016 Feb;107(2):140-8.
Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can eradicate CML leukemia-initiating cells (CML-LICs). However, little is known about the therapeutic benefits such CML-LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW-7197, an orally bioavailable transforming growth factor-beta signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML-LICs in vivo. Compared to TKI treatment alone, administration of TKI plus EW-7197 to CML-affected mice significantly delayed disease relapse and prolonged survival. Notably, combined treatment with EW-7197 plus TKI was effective in eliminating CML-LICs even if they expressed the TKI-resistant T315I mutant BCR-ABL1 oncogene. Collectively, these results indicate that EW-7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML-LICs.
TGF-beta Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1alpha-Induced Epithelial Mesenchymal Transition.[Pubmed:26845171]
Cell Physiol Biochem. 2016;38(2):571-88.
BACKGROUND/AIMS: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1alpha activates hepatic stellate cells (HSCs) and increases transforming growth factor-beta (TGF-beta) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-beta type I receptor kinase, EW-7197, on HIF1alpha-derived TGF-beta signaling in cholestatic liver fibrosis. METHODS: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1alpha-derived TGF-beta signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. RESULTS: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1alpha-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1alpha-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. CONCLUSION: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1alpha-induced TGF-beta signaling.
EW-7197, an activin-like kinase 5 inhibitor, suppresses granulation tissue after stent placement in rat esophagus.[Pubmed:28137596]
Gastrointest Endosc. 2017 Jul;86(1):219-228.
BACKGROUND AND AIMS: Self-expanding metallic stent (SEMS) placement is a well-established method for treating malignant esophageal strictures; however, this procedure has not gained widespread acceptance for treating benign esophageal strictures because of granulation tissue formation. The aim of the present study was to investigate whether EW-7197, a novel per-oral transforming growth factor-beta type I receptor kinase inhibitor, suppressed granulation tissue formation after SEMS placement in the rat esophagus. METHODS: Sixty rats underwent SEMS placement and were randomly divided into 4 groups. Group A (n = 20) received vehicle-treated control for 4 weeks. Group B (n = 20) received 20 mg/kg/day EW-7197 for 4 weeks. Group C (n = 10) received 20 mg/kg/day EW-7197 for 4 weeks followed by vehicle-treated control for 4 weeks. Group D (n = 10) received 20 mg/kg/day EW-7197 for 8 weeks. RESULTS: SEMS placement was technically successful in all rats. Eleven rats, however, were excluded because of stent migration (n = 9) and procedure-related death (n = 2). The luminal diameter in group A was significantly smaller than those in groups B, C, and D (all P < .001). The percentage of granulation tissue area, number of epithelial layers, thickness of submucosal fibrosis, percentage of connective tissue area, and degree of collagen deposition were significantly higher in group A than in groups B, C, and D (all P < .001); however, there were no significant differences among groups B, C, and D. EW-7197 decreased the expression levels of phospho-Smad 3, N-cadherin, fibronectin, alpha-smooth muscle actin, and transforming growth factor-beta1 and increased the expression level of E-cadherin (all P < .01). CONCLUSIONS: EW-7197 suppressed granulation tissue formation after SEMS placement in the rat esophagus.
