• Motowo Nakajima and Wakako Toga.
• Novartis Pharma KK, Tsukuba Research Institute, Ibaraki, Japan. motowo.nakajima@pharma.novartis.com
• Nippon Yakurigaku Zasshi. 2003 Dec 1; 122 (6): 482-90.

AbstractThe 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.

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