A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant Cmls

Because it is now apparent that a significant proportion of patients chronically treated with imatinib develop resistance due to the acquisition of mutations in the kinase domain of BCR-ABL our aim was to generate a potent inhibitor of BCR-ABL by targeting regions outside the ATP binding site of this enzyme as these compounds offer the potential to be unaffected by mutations that make CML cells resistant to imatinib. Screening of a novel library of small molecule kinase inhibitors which are unrelated to ATP or other purine and pyrimidine nucleosides using the high through-put assay led to the identification of three six new compounds series. Of these three compounds were found to be most active against all of the imatinib-resistant forms of BCR-ABL including the T3151 mutation in vitro and in vivo assays. In addition these compounds were also found to inhibit the proliferation of and induce apoptosis of leukemic cell lines that express the V617F mutant form of JAK2 and establish their utility for the treatment of myeloproliferative disorders arising due to mutations in JAK2. We provide a detailed description of their biological activity and mechanism action of these compounds.