Current progress towards the development of tyrosine kinase inhibitors as anticancer agents

Abstract

Tyrosine kinases (TKs) are a large subfamily of the largest known gene family, the kinases, of which the human genome is now estimated to contain in excess of 2,000 [1]. TKs catalyse the phosphorylation of the phenolic hydroxyl of tyrosine. Phosphorylation of proteins is the commonest form of reversible post-translational modification, and is the predominant way of transducing signals within the cell. TK activity appears to be the predominant way that proliferative signalling is passed through the cell membrane and into cells. One might expect overactivity of TKs to cause abnormal proliferation, and indeed kinases are the majority of all known oncogenes, and overphosphorylation is a hallmark of all cancer cells. Inhibitors of oncogenic TKs of great potency and selectivity have been developed, along with many, at least superficially, inferior agents, and excellent in vivo activity has been revealed for some of these compounds. Currently, several agents are in clinical trials and initial results should be forthcoming before the next review in this series is written.