Medline ® Abstract for Reference 1
of 'Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia'
Overriding imatinib resistance with a novel ABL kinase inhibitor.
Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL
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.
Division of Hematology and Oncology, Department of Medicine, The David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.