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 understandi ng that a number of distinct tyrosine kinases play roles in diverse but fun damentally important aspects of tumor progression (growth, survival, metast asis and angiogenesis). The second is the discovery that small molecule com pounds have the capacity to potently and selectively inhibit the biochemica l function of tyrosine kinases by competing for ATP binding at the enzyme c atalytic site. These observations have been conjoined in major efforts to b ring forward into clinical development novel cancer drugs with the potentia l to provide both clinical efficacy and improved tolerability. The focus of this review is on the development of small molecule tyrosine kinase inhibi tors, and does not extend to other approaches that could be applied to disr upt the same pathways in clinical tumors (receptor and/or ligand-competitiv e antibodies, intrabodies, antisense ribonucleotides, ribozymes, phosphatas e inhibitors or SH2/SH3-directed agents). Selected tyrosine kinase inhibito rs, 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 co mpounds are to be developed into clinically useful cancer chemotherapeutic agents.