Oral, potent and selective TGFBRI (ALK5) inhibitor

TGF-β Signaling

Mechanism of Action of Vactosertib

Vactosertib (TEW-7197) blocks the TGF-β signaling pathway by inhibiting phosphorylation of TGF-β receptor I (ALK5). Vactosertib not only inhibits cancer cell growth, stem cancer cell induction and metastasis, but it also demonstrated synergistic effects in combination with chemotherapy 1) and showed dramatic efficacy in tumor shrinkage when treated with an immune checkpoint blockade.

In the 1970s, the hormone and hormone-like-growth factors were considered to be cancer-related molecules. At that time, the sarcoma growth factor (SGF) was discovered, and the transforming activity of SGF was discovered by Anita Roberts Group at the National Institutes of Health (NIH). They found that SGF can be classified as either TGF-α or TGF-β. TGF-β was initially researched as a wound healing factor 2), however, subsequent research findings highlighted the significance of TGF-β’s role in cancer.

TGF-β signaling can promote invasion and metastasis during the later stages of carcinoma progression. During tumor progression, tumor cells frequently lose the growth-inhibitory response to TGF-β due to an increased expression of TGF-β in the tumor microenvironment. Cell-autonomous TGF-β signaling can cause epithelial–mesenchymal transitions (EMT) in carcinoma cells, which increase invasion and metastasis 3).

Due to significance of TGF-β signaling in cancer, Vactosertib has the potential to be used as an anti-cancer drug for all kinds of human tumors. A Phase 1 clinical trial was completed in the US and Phase 2 trials are currently ongoing in the US and Korea.

  • 1) Lab Invest. 2005 Apr;85(4):512-21.
  • 2) Proc Natl Acad Sci U S A. 1983 Oct;80(20):6264-8.
  • 3) Cell. 2008 May 16;133(4):704-15