Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents

Numerous small molecule synthetic tyrosine kinase inhibitors are in clinical development for the treatment of human cancers. These fall into three broad categories: inhibitors of the epidermal growth factor receptor tyrosine kinase family (e.g., Iressa(Tm) and Tarceva(TM)), inhibitors of the split kinase domain receptor tyrosine kinase subgroup (e.g., PTK787/ZK 222584 and SU1 1248) and inhibitors of tyrosine kinases from multiple subgroups (e.g., Gleevec(TM)). In addition, agents targeting other tyrosine kinases implicated in cancer, such as Met, Tie-2 and Src, are in preclinical development. As experience is gained in the clinic, it has become clear that unleashing the full therapeutic potential of tyrosine kinase inhibitors will require patient preselection, better assays to guide dose selection, knowledge of mechanism-based side effects and ways to predict and overcome drug resistance.