Disruption of Angiogenesis and Tumor Growth with New Orally Active Drug

Strategic Insights -

Researchers have published a report in the Proceedings of the National Academy of Sciences of the United States of America detailing the discovery of a new drug that stabilizes the inactive state of PDGFRbeta/B-RAF, leading to disruption of angiogenesis and tumor growth. This breakthrough in cancer research has significant implications for the treatment of various cancer indications. The study, conducted by E.A. Murphy and colleagues at the University of California, Moores Cancer Center, demonstrates the potential of targeting kinases in the inactive state to develop selective inhibitors.

Key Takeaways:

  • The study highlights the importance of kinase inhibitors in cancer treatment, with several already approved for various cancer indications.
  • The researchers used a rational design approach to generate a series of selective type II inhibitors of PDGFRbeta and B-RAF, which demonstrated synergistic antiangiogenic activity in zebrafish and murine models of angiogenesis.
  • The lead compound was selected as an orally active molecule with favorable pharmacokinetic properties, demonstrating target inhibition in vivo and suppression of murine orthotopic tumors in both the kidney and pancreas.
  • The discovery of this new drug has significant implications for the treatment of various cancer types, with the potential to disrupt angiogenesis and tumor growth.
  • The researchers concluded that targeting kinases in the inactive state provides an alternative approach for developing selective inhibitors that are physiologically active.

Statistics:

  • 7 out of 10 cancer-related deaths are attributed to metastasis, making targeted therapies essential for improving patient outcomes.
  • Neovascularization is a critical process in cancer progression, with angiogenic factors such as VEGF playing a key role.
  • The use of kinase inhibitors has been a major focus of drug development in recent years, with several already approved for cancer indications.
  • The lead compound was screened for antivascular activity in both cell-based models and a Tg(fli1-EGFP) zebrafish embryogenesis model, demonstrating synergistic antiangiogenic activity.
  • The researchers demonstrated target inhibition in vivo, suppressing murine orthotopic tumors in both the kidney and pancreas.

Sources:

  • Murphy, E.A., et al. (2010). Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRbeta/B-RAF. Proceedings of the National Academy of Sciences of the United States of America, 107(9), 4299-304.
  • Enzyme Research.