The recognition that the BCR-ABL gene and corresponding protein with deregulated tyrosine kinase (TK) activity is crucial for malignant transformation in chronic myeloid leukemia (CML), led to the synthesis of the smallmolecule drugs designed to interfere with BCR-ABL TK activation. The first tyrosine kinase inhibitor (TKI) was imatinib mesylate, introduced into clinical practice in 1998, which became the first choice drug in chronic phase CML. However, approximately 20-25% of patients initially successfully treated with imatinib will need alternative therapy because of unsatisfactory therapeutic results due to drug resistance. The risk of resistance is even higher in patients in advanced phases of CML. Resistance to imatinib is in about 35%-45% attributed to selection of clones expressing mutant forms of BCRABL which impair imatinib binding but preserve the kinase activity. The availability of second-generation TKIs has provided a new therapeutic option for patients with imatinib resistance. Among them, dasatinib is the first to be approved in the US and European Union for CML patients resistant or intolerant to imatinib. This drug is a dual SRC/ABL kinase inhibitor, 325-fold more potent than imatinib against cells expressing wild-type BCR-ABL and active in most clinically relevant BCR-ABL mutations, except highly resistant T315I. Several clinical trials have demonstrated that dasatinib is effective and generally well tolerated in imatinib resistant or intolerant CML and represents a promising therapeutic option for these patients.
Keywords: Chronic myeloid leukemia, tyrosine kinase inhibitors, dual SRC/ABL kinase inhibitor, dasatinib, imatinib, AGP, A-loop, AP, ATP, AUC, BP, CCyR Comp, CFU, CHR, CML, CMoR, CP, CyR, EGFR, HR, IC50, JNK, MAPK, MCyR, MMoR, OS, P-gp, PCyR, PDGFR, PFS, Ph, PI3K, P-loop, SFKs, STAT5, TK, TKI, piperazin-1-yl-2-methylpyrymidin-4-ylamino thiazole-5-carboxamide, family kinase (SFks), ABL kinase domain, BCR-ABL mutants, F317L, Threonine315, M351T, colony-forming-unit (CFU) assay, IC50 0.2 nM), Lck (IC50 1.1 nM), Src (IC50 0.55 nM), Yes (IC500.41 nM), hOCT1 (human organic cation transporter 1), CYP3A4 enzyme