EW-7197 Hydrochloride

Vactosertib Hydrochloride (EW-7197 Hydrochloride) is a small-molecule ATP-competitive inhibitor of TGFβRI (ALK5) with an IC50 of 12.9 nM.

Signaling Pathways >> TGF-beta/Smad >> TGF-β Receptor

Research Areas >> Cancer

IC50: 12.9 nM (ALK5)[1]

Kinase assays demonstrate that Vactosertib (EW-7197) is a small-molecule ATP-competitive inhibitor of TGFβRI (ALK5) with an IC50 of 12.9 nM. The IC50 values of Vactosertib against p38a is 1775 nM. Vactosertib also inhibits ACVR1B/ALK4 and the IC50 value against it is determined to be 17.3 nM. Vactosertib blocks the TGFβ-induced phosphorylation of Smad2 or Smad3 in a dose-dependent manner in 4T1 cells, and MDA-MB-231 cells. Vactosertib suppresses the TGFβ-induced nuclear translocation of Smad2/3 in 4T1 cells and MCF10A cells[1]. Vactosertib (EW-7197) treatment also dramatically reduces the colony-forming capacity of CML-MPPs in vitro in a dose-dependent manner[2].

Vactosertib (EW-7197; 40 mg/kg) treatment of MMTV/c-Neu transgenic mice significantly reduces lung metastasis by 60% compare with the control. Treatment with Vactosertib decreases the number of metastatic nodules compare with that in the Veh-treated control group by 53% and 68% (5 and 20 mg/kg). Vactosertib (0.625, 1.25, 2.5, or 5 mg/kg; five times/week) inhibits lung metastasis and increases the survival of 4T1-Luc cells, in a dose-dependent manner. Vactosertib also prolongs the survival of BALB/c mice orthotopically bearing 4T1 tumors by 36% at doses of 2.5 and 5 mg/kg[1].

To determine colony-forming capacity after a combination treatment of Vactosertib plus IM, or Vactosertib plus ponatinib, freshly isolated CML-LICs on OP-9 stromal cells are cocultured in the presence of DMSO or Vactosertib for 24 h. Cells are then treated with additional DMSO, 1 μM IM, or 1 μM ponatinib and cultured for another 2 days (total, 3 days). Colonies are counted 7 days later[2].

BALB/c mice are used and maintained in a temperature-controlled room (at 21°C) and supplied with food and water. 4T1-luc cells are suspended in saline and injected into the tail veins of female BALB/c mice (50 μL/mouse; day 0). Artificial gastric fluid (Veh) or Vactosertib (0.625, 1.25, 2.5, or 5 mg/kg) dissolved in Veh is administered orally to mice five times per week from day 0 until death (n=13/group). On day 15, surviving mice are analyzed using an in vivo imaging system to compare metastases in the lungs. Luciferase-positive 4T1 cells are imaged with the IVIS-200 system. The captured images are quantified using the Living Image Software package[1].

[1]. Son JY, et al. EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis. Mol Cancer Ther. 2014 Jul;13(7):1704-16.

[2]. Naka K, et al. Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells. Cancer Sci. 2016 Feb;107(2):140-8.

SB431542 | Galunisertib (LY2157299) | A 83-01 | LY2109761 | LDN193189 | RepSox | SB525334 | Vactosertib (TEW-7197) | DMH-1 | GW788388 | LY364947 | SB505124 | LY3200882 | H-Leu-Ser-Lys-Leu-NH2 trifluoroacetate salt | ITD-1