Anti-tumor Activity of Novel Compounds Targeting BCR-ABL, c-SRC and BCR-ABLT315I in Chronic Myelogenous Leukemia
2013
Chronic myelogenous leukemia (CML) is a hematological stem-cell disorder characterized by the expression of the BCR-ABL fusion protein, a constitutively active tyrosine kinase that causes pathogenesis. The development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene has proven an effective approach to treat CML, but a non-negligible proportion of patients develop a resistance to this class of drugs. Of note, the T315I mutant of BCR-ABL is resistant to all known TKIs, with the noticeable exception of ponatinib. To address this unmet medical need, a new series of compounds was designed and tested for anti-tumor effects against BCR-ABL T315I CML. The effects of three OriBase Pharma compounds (OR1001, OR1002 and OR1003) on the kinase activity of wild-type and mutant BCR-ABL proteins, on cell proliferation and on the growth of subcutaneous xenografts of CML cells in athymic mice were investigated. In vitro , the three compounds were potent inhibitors of both ABL and c-SRC kinases and of the main mutants of ABL, including T315I. The three compounds inhibited the proliferation of cell lines expressing the wild-type and several mutated forms of BCR-ABL, including T315I. Finally, in a mouse xenograft model, OR1001, was found to significantly reduce tumor growth. These data support the potential of OR1001 as an effective therapy for the treatment of de novo and TKI-resistant patients.
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