Novel Substrate Competitive Bcr-Abl Inhibitor Active Against Gleevec-Resistant CM

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Imatinib, which is an inhibitor of BCR-ABL tyrosine kinase and used for the treatment of human CML, has been a spectacular success. However, a significant proportion of patients chronically treated with imatinib develop resistance due to acquisition of mutations in the kinase domain of BCR-ABL. We have recently developed a compound (ON012380) that binds to BCR-ABL at a site different from imatinib and induces apoptosis of Ph+ CML cells at a concentration of 5-10 nM (which is 10-50 fold more potent than imatinib). More interestingly, this compound was found to be very effective in inducing the death of all of the imatinib-resistant mutants of CML identified so far. In this application, we propose to carry out a detailed biochemical characterization of the mechanism of action of this compound and the nature of signaling pathways that are affected by this compound. The aims are:1. To determine the kinetics of inhibition of BCR-ABL by ON012380 and carry out in vitro screen of mutagenizedBCR-ABL clones to gain an understanding of the amino acid substitutions that are likely to imapir the binding of ON012380. 2. To determine the effects of ON012380 on (a) wild-type and imatinib-resistant mutants of BCR-ABL on the kinase activity; (b) downstream signaling such as MAPK, AKT and STATS activation (c) cell cycle progression; and (d) the nature of apoptotic pathways activated in tumor cells that express wild-type or mutant BCR-ABL protein. 3. Determine whether ON012380 induces cell death of Lynoverexpressing, imatinib resistant cells and if so, determinethe mechanismof action. 4. Conduct pharmacokinetic studies by the route and schedule used for efficacy studies, and 5. Conduct efficacy trials in established xenograft models of CML.