The long term objective of this program is to identify and develop an angiostatic compound useful in cancer treatment. The rationale is to develop a dual inhibitor of the heparin binding endothelial growth factors bFGF and VEGF. Phase I goals were to validate methods to synthesize and identify growth factor-heparin binding antagonists which block endothelial cell proliferation. Phase I work not only identified a dual bFGF and VEGF inhibitor from a pilot heparin mimetic combinatorial library, but showed the compound to be active in vitro and in vivo to block endothelial proliferation. Thus, the primary goal was achieved and methods were validated for continuing the objective of discovering optimal growth factor antagonists that have angiostatic activity. Current studies are focused on identifying additional antagonists so that medicinal chemistry (analog synthesis) can be based on multiple active structures. Current methods for combinatorial compound synthesis allow rapid iterative compound improvements and scale-up for in vivo testing in both mechanism and disease based models. The application proposes to use these validated synthesis and screening methods, together with toxicity and tumor models in vivo to complete the identification of optimal compounds suitable for development as treatments for cancer and related proliferative disorders.
Not available.
