Tyrosine kinases in disease: overview of kinase inhibitors as therapeutic agents and current drugs in clinical trials.

Tyrosine kinases, first described as oncogenes, have been shown to play a role in normal cellular processes. Aberrations in tyrosine kinase activity lead to disease states. For fifteen years it has been postulated that the inhibition of tyrosine kinases may have therapeutic utility and the design and testing of inhibitors have been major focuses of research and development in both academic institutions and pharmaceutical companies. While early research focused on developing chemical entities that mimic phosphotyrosine, later research has focused on developing competitive adenosine triphosphate (ATP) inhibitors with various levels of selectivity on kinase targets. This review focuses on a discussion of tyrosine kinases thought to be important in disease, including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial cell growth factor (VEGF), epidermal growth factor (EGF) receptors, HER-2 and Src. In addition, the classes of inhibitors designed to affect these targets and that have overcome research and development challenges and entered clinical trials are discussed. These include isoxazole, quinazoline, substituted pyrimidines and indolinone compounds, all of which are in clinical trials or near clinical development by SUGEN, Zeneca, Novartis, Pfizer and Parke-Davis. A summary of the chemistry and activity of these agents is provided.