Isolation of Focal Adhesion Kinase-specific Modulators

Focal Adhesion Kinase (FAK) plays an important role in transducing signals generated by cellular adhesion molecules regulating cellular migration, growth and survival. It is becoming clear that FAK also relays angiogenic signals from multiple cell surface proteins. Inhibition of FAK by expression of the noncatalytic carboxyl-terminal protein-binding domain of FAK, known as FRNK (FAK-related, non-kinase) reduces vascular endothelial growth factor (VEGF)- and vascular cell adhesion molecule (VCAM)-induced angiogenesis, as well as platelet-derived growth factor (PDGF)-induced proliferation and migration. Additionally, embryos of FAK-knockout mice demonstrate impaired blood vessel formation most likely due to migratory defects. Thus, FAK activity appears to be essential for angiogenesis. This emerging role for FAK suggests that a small-molecule inhibitor of FAK would disrupt angiogenic signaling. Additionally, the use of FRNK has demonstrated that FAK inhibition may enhance the cytotoxic effects of chemotherapeutic agents on transformed cells and inhibit proliferation of tumor cells. Thus, a small-molecule, FAK-specific inhibitor would have many applications. We have developed high throughput screening assays for identification of small-molecule, kinase-specific inhibitors. We will screen an extensive natural products library derived from plants of rare genera to isolate and identify FAK-specific inhibitors.