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Science 289 (5486): 1938-1942

Copyright © 2000 by the American Association for the Advancement of Science

Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase

Thomas Schindler,1 William Bornmann,3 Patricia Pellicena,4 W. Todd Miller,4 Bayard Clarkson,3 John Kuriyan12*

The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. Critical to the binding of STI-571 is the adoption by the kinase of an inactive conformation, in which a centrally located "activation loop" is not phosphorylated. The conformation of this loop is distinct from that in active protein kinases, as well as in the inactive form of the closely related Src kinases. These results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.

1 Laboratories of Molecular Biophysics and
2 Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
3 Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
4 Department of Physiology and Biophysics, School of Medicine, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
*   To whom correspondence should be addressed. E-mail: kuriyan{at}rockefeller.edu

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Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia.
T. O'Hare, C. A. Eide, and M. W. N. Deininger (2007)
Blood 110, 2242-2249
   Abstract »    Full Text »    PDF »
Progressive Thoughts about Progressive Disease.
N. P. Shah (2007)
Clin. Cancer Res. 13, 5229-5231
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Crystal Structure of the T315I Abl Mutant in Complex with the Aurora Kinases Inhibitor PHA-739358.
M. Modugno, E. Casale, C. Soncini, P. Rosettani, R. Colombo, R. Lupi, L. Rusconi, D. Fancelli, P. Carpinelli, A. D. Cameron, et al. (2007)
Cancer Res. 67, 7987-7990
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The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib.
O. Hantschel, U. Rix, U. Schmidt, T. Burckstummer, M. Kneidinger, G. Schutze, J. Colinge, K. L. Bennett, W. Ellmeier, P. Valent, et al. (2007)
PNAS 104, 13283-13288
   Abstract »    Full Text »    PDF »
Exploring sequence-structure relationships in the tyrosine kinome space: functional classification of the binding specificity mechanisms for cancer therapeutics.
G. M. Verkhivker (2007)
Bioinformatics 23, 1919-1926
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Sorafenib Inhibits Imatinib-Resistant KIT and Platelet-Derived Growth Factor Receptor {beta} Gatekeeper Mutants.
T. Guida, S. Anaganti, L. Provitera, R. Gedrich, E. Sullivan, S. M. Wilhelm, M. Santoro, and F. Carlomagno (2007)
Clin. Cancer Res. 13, 3363-3369
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c-Abl Tyrosine Kinase and Inhibition by the Cancer Drug Imatinib (Gleevec/STI-571).
B. Nagar (2007)
J. Nutr. 137, 1518S-1523S
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Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study.
A. Ray, S. W. Cowan-Jacob, P. W. Manley, J. Mestan, and J. D. Griffin (2007)
Blood 109, 5011-5015
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Rational Drug Redesign to Overcome Drug Resistance in Cancer Therapy: Imatinib Moving Target.
A. Fernandez, A. Sanguino, Z. Peng, A. Crespo, E. Ozturk, X. Zhang, S. Wang, W. Bornmann, and G. Lopez-Berestein (2007)
Cancer Res. 67, 4028-4033
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c-Abl Tyrosine Kinase Activates p21 Transcription Via Interaction with p53.
Y. Jing, M. Wang, W. Tang, T. Qi, C. Gu, S. Hao, and X. Zeng (2007)
J. Biochem. 141, 621-626
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Alterations of Ceramide/Sphingosine 1-Phosphate Rheostat Involved in the Regulation of Resistance to Imatinib-induced Apoptosis in K562 Human Chronic Myeloid Leukemia Cells.
Y. Baran, A. Salas, C. E. Senkal, U. Gunduz, J. Bielawski, L. M. Obeid, and B. Ogretmen (2007)
J. Biol. Chem. 282, 10922-10934
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Resistance to c-KIT kinase inhibitors conferred by V654A mutation.
K. G. Roberts, A. F. Odell, E. M. Byrnes, R. M. Baleato, R. Griffith, A. B. Lyons, and L. K. Ashman (2007)
Mol. Cancer Ther. 6, 1159-1166
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Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias.
E. Weisberg, L. Catley, R. D. Wright, D. Moreno, L. Banerji, A. Ray, P. W. Manley, J. Mestan, D. Fabbro, J. Jiang, et al. (2007)
Blood 109, 2112-2120
   Abstract »    Full Text »    PDF »

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