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Medline ® Abstract for Reference 29

of 'Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy'

29
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Overriding imatinib resistance with a novel ABL kinase inhibitor.
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Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL
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Science. 2004;305(5682):399.
 
Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL-driven disease and inhibits proliferation of BCR-ABL-positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor resistance can guide the design of second-generation targeted therapies.
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Division of Hematology and Oncology, Department of Medicine, The David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
PMID