Protein tyrosine kinases as therapeutic targets in cancer chemotherapy and recent advances in the development of new inhibitors

Abstract

Future approaches to cancer chemotherapy will inevitably include ways to modulate the function of oncogenes, suppressor genes or components of mitogenic or cell cycle signal transduction. One set of likely targets for therapeutic intervention are tyrosine kinases. Over the past decade, tyrosine phosphorylation/dephosphorylation has irrefutably been shown to be intimately involved in growth regulation, mitogenesis and cell cycle progression. Many of the known tyrosine kinases are encoded for by proto-oncogenes, and transforming mutations or uncontrolled activity of these enzymes have been observed in tumours. Certain growth factors known or suspected to participate in autocrine mechanisms of tumour propagation bind to receptors having tyrosine kinase activity and there now exists a significant amount of clinical data to implicate a role for many of these enzymes in the development or progression of disease in cancer patients. Throughout the last decade many inhibitors of tyrosine kinases have been discovered both as natural products and by rational synthetic chemistry. In recent years, considerable progress has been made to increase inhibitory potency and specificity of inhibitors toward tyrosine kinases as well as to attain specific inhibition of these enzymes in viable cells. One dubious aspect of this area of research has been the lack of experimental results to demonstrate a clear antitumour effect in vivo by these inhibitors. This may indeed reflect the newness of the area as well as perhaps an ignorance of how to properly utilise such novel potential drugs. Clearly, major advances have been made in the area of developing inhibitors of tyrosine kinases but the next essential objective is a firm demonstration of in vivo antitumour activity.