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Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
Neil P. Shah,1
Chris Tran,1,2
Francis Y. Lee,3
Ping Chen,3
Derek Norris,3
Charles L. Sawyers1,2*
Abstract:
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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27, 469-471
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Functional Analysis of Epidermal Growth Factor Receptor (EGFR) Mutations and Potential Implications for EGFR Targeted Therapy.
R. K. Kancha, N. von Bubnoff, C. Peschel, and J. Duyster (2009)
Clin. Cancer Res.
15, 460-467
|Abstract »|Full Text »|PDF »
A conserved protonation-dependent switch controls drug binding in the Abl kinase.
Y. Shan, M. A. Seeliger, M. P. Eastwood, F. Frank, H. Xu, M. O Jensen, R. O. Dror, J. Kuriyan, and D. E. Shaw (2009)
PNAS
106, 139-144
|Abstract »|Full Text »|PDF »
Crystal Structures of the Lyn Protein Tyrosine Kinase Domain in Its Apo- and Inhibitor-bound State.
N. K. Williams, I. S. Lucet, S. P. Klinken, E. Ingley, and J. Rossjohn (2009)
J. Biol. Chem.
284, 284-291
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Toward a Cure For Chronic Myeloid Leukemia.
T. O'Hare and M. W. Deininger (2008)
Clin. Cancer Res.
14, 7971-7974
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Translation of the Philadelphia chromosome into therapy for CML.
