Vascular endothelial growth factor (VEGF) inhibition by small molecules

Angiogenesis is essential for primary tumours to grow and metastasise, and is driven by the production of positive angiogenic factors. The Vascular Endothelial Growth Factor (VEGF) family is central to the process of angiogenesis and comprises 5 molecules designated A, B, C, D and E. VEGF is overexpressed in several solid malignancies. The actions of VEGF are mediated through receptors possessing tyrosine kinase activity: VEGFR-1 (Flt-1), VEGFR-2 (Kdr/Flk-1) and VEGFR-3 (Flt-4). Anti-VEGF strategies include the use of antibodies to VEGF or its receptors, the use of ribozymes to decrease receptor expression, and the use of inhibitors of tyrosine kinase to reduce receptor activation and downstream signalling. The focus of this review is small molecule inhibitors of VEGF receptors which target their intrinsic tyrosine kinase activity. The clinical development of the following agents is discussed: SU5416, SU11248, SU6668, PTK/ZK, ZD6474.