Since the initial discovery of tyrosine-specific protein kinases encoded by transforming viruses and their normal cellular homologues, there has been a great deal of interest in understanding their role in cancer and exploring their potential as therapeutic targets. Several approaches confirmed the role of tyrosine kinases in virtually every aspect of cellular transformation including cell cycle progression, increased survival in response to apoptotic challenge, neovascularization, and aberrant gene expression (for review, see Ref. 1). This information suggested that the diverse spectrum of tyrosine kinases and their association with specific malignancies offered multiple targets for chemotherapeutic intervention. However, exploitation of these enzymes as specific tumor targets has only recently been realized, and clinical application of tyrosine kinase-targeted therapy is a new and growing field (2–4). Initial discovery of small molecules that interfered with ATP binding or utilization represented a major breakthrough in tyrosine kinase-targeted therapy (5). Subtle but measurable distinctions in the ATP binding pocket of tyrosine kinases were exploitable, and specificity for individual kinases (or related enzymes) could be engineered into small molecules with characteristics of conventional chemotherapeutic agents [molecular size, bioavailability, and cell and tissue uptake (5–8)]. The key to successful development of small molecular kinase inhibitors has been in providing selective and potent inhibition of an oncogenic target. In some cancers, unregulated or aberrant expression of a single tyrosine kinase underlies transformation (9, 10), providing great opportunities for targeted therapy with tyrosine kinase inhibitors.

CML2 is characterized in 95% of patients by the presence of the Philadelphia chromosome, representing a reciprocal translocation of chromosomes 9 and 22 (11, 12). This translocation results in altered control of the c-abl tyrosine kinase and expression of a protein, termed bcr-abl, with exons derived from the c-abl gene and bcr locus (12). The resultant chimeric protein expresses unregulated tyrosine kinase activity, and studies have shown that its kinase activity is important in the etiology of CML and other diseases (13). Therefore, bcr-abl kinase inhibition may have a direct impact on CML and other diseases. After collection of the structural, enzymatic, and molecular characteristics of tyrosine kinases, a 2-phenylaminopyrimide