Vactosertib (EW-7197, TEW-7197)

Description

APIM050415: Vactosertib (EW-7197, TEW-7197) is a potent, orally active and ATP-competitive activin receptor-like kinase 5 (ALK5) inhibitor with an IC₅₀ of 12.9 nM. Vactosertib also inhibits ALK2 and ALK4 (IC₅₀ of 17.3 nM) at nanomolar concentrations. Vactosertib has potently antimetastatic activity and anticancer effect.

CAS No.: 1352608-82-2
IUPAC/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
Molecular Formula: C₂₂H₁₈FN₇
Molecular Weight: 399.42
Purity: >99% Purity
QC: Achiral and Chiral HPLCs, MS, NMR, and Quantitative Elemental Analysis Report
Solubility: Soluble in DMSO
Storage: Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).
Note: Please contact us for COA, Spectra, and SDS information.

Background Information:

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. Vactosertib (EW-7197, TEW-7197) (CAS No. 1352608-82-2) 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.

Target: ALK5

IC₅₀: 12.9 nM

In Vitro: Vactosertib (EW-7197, TEW-7197) (10-1000 nM; 30 minutes; 4T1 cells) treatment blocks the TGFβ-induced phosphorylation of Smad2 or Smad3 in a dose-dependent manner in 4T1 cells. [1]
Vactosertib suppresses the TGFβ-induced nuclear translocation of Smad2/3 in 4T1 cells and MCF10A cells. The IC₅₀ value of Vactosertib on pSmad3 in 4T1 cells is 10-30 nM. [1]
Vactosertib abrogates TGFb1-induced tumor cell migration and invasion. [1]
TGFβ1 downregulated the mRNA level of CDH1 and upregulated the mRNA levels of FN1, HMGA2 (high-mobility group AT-hook 2), SNAI1, and SNAI2 (Snail family zinc finger 1 and 2, respectively). Moreover, Vactosertib abolishes the TGFβ1-induced effects on genes related to epithelial-to-mesenchymal transition (EMT). [1]

In Vivo: Vactosertib (EW-7197, TEW-7197) (40 mg/kg; intraperitoneal injection; every other day; for 10 weeks; MMTV/c-Neu female mice) treatment inhibits Smad/TGFβ signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice. [1]
Vactosertib also inhibits the epithelial-to-mesenchymal transition (EMT) in both TGFβ-treated breast cancer cells and 4T1 orthotopic-grafted mice. Furthermore, Vactosertib enhances cytotoxic T lymphocyte activity in 4T1 orthotopic-grafted mice and increased the survival time of 4T1-Luc and 4T1 breast tumor-bearing mice. [1]

What is the solubility of Vactosertib (EW-7197, TEW-7197) in vitro?
DMSO: > 100 mg/mL

What is the solubility of Vactosertib (EW-7197, TEW-7197) in vivo?
1. DMSO, PEG300, Tween-80, and saline
Please add 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline in order, solubility: 2.5 mg/mL.
2. DMSO and 20% SBE-β-CD in saline
Please add 10% DMSO and 90% (20% SBE-β-CD in saline) in order, solubility: ≥ 2.5 mg/mL.
3. DMSO and corn oil
Please add 10% DMSO and 90% corn oil in order, solubility: ≥ 2.5 mg/mL.

Reference:
[1]. Son, J. Y. et al. “EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis”, Mol. Cancer Ther., 2014, 13, 1704-16.
[2]. Kim, J. et al. “Combination of TEW-7197 and adoptively transferred NK cells leads to Improved Antitumor Responses in vivo”, J. Immunol., 2020, 204 (1 Supplement), 241.45
[3]. Park, S. A. et al. “TIMP-1 mediates TGF-β-dependent crosstalk between hepatic stellate and cancer cells via FAK signaling”, Sci. Rep., 2015, 5, 16492.
[4]. Han, K. et al. “EW-7197 eluting nano-fiber covered self-expandable metallic stent to prevent granulation tissue formation in a canine urethral model”, Plos One 2018, https://doi.org/10.1371/journal.pone.0192430.
[5]. Yoon, S.-H. et al. “EW-7197, a Transforming Growth Factor-Beta Type I Receptor Kinase Inhibitor, Ameliorates Acquired Lymphedema in a Mouse Tail Model”, Lymphat. Res. Biol., 2020, https://doi.org/10.1089/lrb.2018.0070
[6]. Kim, B.-G. et al. “Abstract 2647: TGF-β type I receptor inhibitor (TEW-7197) diminishes myeloma progression by multiple immunomodulatory mechanisms in combination with ixazomib”, Cancer Res., 2017, DOI: 10.1158/1538-7445.AM2017-2647.
[7]. Malek, E. et al. “Preclinical Studies and a Phase I Trial of the TGF-β Receptor Inhibitor, Vactosertib (TEW-7197), in Combination with Pomalidomide in Patients with Multiple Myeloma Refractory to Bortezomib or Lenalidomide”, Blood, 2018, https://doi.org/10.1182/blood-2018-99-112449
[8]. Song, K.-M. et al. “AB083. TEW-7197, a novel orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaque in a rat model of Peyronie’s disease”, Transl. Androl. Urol., 2018, doi: 10.21037/tau.2018.AB083
[9]. Kim, B.-G. et al. “Vactosertib, a TGF-ß Receptor I Kinase/ALK5 Inhibitor, Diminishes Tumor Progression and Bone Disease in a Mouse Model of Multiple Myeloma and Overcomes Resistance to Proteasome Inhibitors”, Blood, 2018, https://doi.org/10.1182/blood-2018-99-117852
[10]. Jin, C. H. et al. “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, https://doi.org/10.1021/jm500115w

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Additional information

Size	10 mg, 100 mg, 5 mg, 50 mg

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