Vactosertib

Vactosertib (EW-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^[1][2]. IC50 & Target: IC50: 12.9 nM (ALK5)^[1] In Vitro: Vactosertib (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 (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].