Abstract
Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) originates from multipotential stem cells and is caused by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the fusion protein BCR-ABL, a constitutively activated tyrosine kinase. The discovery of imatinib, which selectively targets BCR-ABL, represents a breakthrough treatment for this disorder. However, emerging evidence indicates that a significant proportion of patients in the early chronic phase of the disease fail to achieve optimal response to imatinib due to innate or acquired drug resistance. Moreover, patients in the accelerated or blast crisis phases of the disease in general respond far less favorably to imatinib therapy. There is an urgent need for improved treatment options for these patient populations. BMS-354825, a dual-selective inhibitor of SRC and ABL kinases has demonstrated promising antileukemic activity in vitro and in vivo against preclinical models of human CML, including several that were resistant to imatinib through a variety of mechanisms (Lee et al., Proceedings of the AACR, 2004; Donato et al., Proceedings of the AACR, 2004;
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