The Philadelphia chromosome found in leukemia cells of chronic myelogenous 
leukemia (CML) patients is produced by translocation between chromosomes 9 and 
22, resulting in expression of a chimera protein of Bcr and Abl kinase in the 
cytoplasm. Bcr-Abl kinase attracted oncology researchers as a molecular target 
for CML therapy, and a variety of small Abl kinase inhibitors were synthesized. 
STI571 (imatinib mesylate) was produced by modification of 
2-phenylaminopyrimidine, a core structure of protein kinase C inhibitor, to 
improve selectivity, stability, solubility, and bioavailability. STI571 
competitively binds to the ATP binding site of Bcr-Abl kinase and inhibits Abl 
tyrosine kinase activity. STI571 showed significant efficacy in the clinical 
study with CML patients at all stages: chronic phase, accelerated phase, and 
blast crisis. More than 90% of the patients showed good hematologic response to 
STI571. STI571 is also a potent inhibitor of a receptor-type c-Kit tyrosine 
kinase. Therefore, STI571 was examined for therapeutic efficacy against 
malignant Gastro-Intestinal Stromal Tumors (GIST), which are mainly caused by 
aberrant expression of a mutated c-Kit that is constitutively active without 
binding of a ligand, stem cell factor (SCF). More than a half of the metastatic 
GIST patients enrolled in the clinical study responded to STI571. Thus, STI571 
is now used as a therapeutic drug for both CML and GIST in more than 80 
countries worldwide. Certain point mutations in the ATP binding site were found 
to be a cause of resistance to STI571 in both Bcr-Abl and c-Kit kinases. 
Therefore, it would be better to make a precise therapeutic strategy with STI571 
based on the gene analysis data. It is also expected that it will be possible to 
design an inhibitor to overcome such resistance by using the structural 
information on the mutants.