Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an anti-angiogenesis agent

Angiogenesis, or the sprouting of new blood vessels, is a central process i n the growth of solid tumors. For many cancers, the extent of vascularizati on of a tumor is a negative prognostic indicator signifying aggressive dise ase and increased potential for metastasis, Recent efforts to understand th e molecular basis of tumor-associated angiogenesis have identified several potential therapeutic targets, including the receptor tyrosine kinases for the angiogenic factor vascular endothelial growth factor (VEGF). Here we re view the approach taken at SUGEN. Inc. to discover and develop small molecu le inhibitors of receptor tyrosine kinases as anti-angiogenic agents. We fo cus on SU5416, a selective inhibitor of VEGF receptors that is currently in clinical development for the treatment of advanced malignancies. Its bioch emical, biological and pharmacological properties are reviewed and clinical implications discussed.