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Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
Neil P. Shah,1Chris Tran,1,2Francis Y. Lee,3Ping Chen,3Derek Norris,3Charles L. Sawyers1,2*
Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec)in chronic myeloid leukemia (CML) occurs through selection fortumor cells harboring BCR-ABL kinase domain point mutationsthat interfere with drug binding. Crystallographic studies predictthat most imatinib-resistant mutants should remain sensitiveto inhibitors that bind ABL with less stringent conformationalrequirements. BMS-354825 is an orally bioavailable ABL kinaseinhibitor with two-log increased potency relative to imatinibthat retains activity against 14 of 15 imatinib-resistant BCR-ABLmutants. BMS-354825 prolongs survival of mice with BCR-ABL–drivendisease and inhibits proliferation of BCR-ABL–positivebone marrow progenitor cells from patients with imatinib-sensitiveand imatinib-resistant CML. These data illustrate how molecularinsight into kinase inhibitor resistance can guide the designof second-generation targeted therapies.
1 Division of Hematology and Oncology, Department of Medicine, The David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. 2 Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. 3 Bristol-Myers Squibb Oncology, Princeton, NJ, USA.
* To whom correspondence should be addressed. E-mail: csawyers{at}mednet.ucla.edu
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