From oncogene to drug: development of small molecule tyrosine kinase inhibitors as anti-tumor and anti-angiogenic agents

The confluence of two distinct but related activities in the past 10 years has dramatically accelerated efforts towards the discovery and development of novel drugs to treat cancer. The first is a rapidly emerging understanding that a number of distinct tyrosine kinases play roles in diverse but fundamentally important aspects of tumor progression (growth, survival, metastasis and angiogenesis). The second is the discovery that small molecule compounds have the capacity to potently and selectively inhibit the biochemical function of tyrosine kinases by competing for ATP binding at the enzyme catalytic site. These observations have been conjoined in major efforts to bring forward into clinical development novel cancer drugs with the potential to provide both clinical efficacy and improved tolerability. The focus of this review is on the development of small molecule tyrosine kinase inhibitors, and does not extend to other approaches that could be applied to disrupt the same pathways in clinical tumors (receptor and/or ligand-competitive antibodies, intrabodies, antisense ribonucleotides, ribozymes, phosphatase inhibitors or SH2/SH3-directed agents). Selected tyrosine kinase inhibitors, known or believed to be in development in cancer treatment trials, are summarized as are some of the key issues that must be addressed if these compounds are to be developed into clinically useful cancer chemotherapeutic agents.