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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}

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M. Puttini, S. Redaelli, L. Moretti, S. Brussolo, R. H Gunby, L. Mologni, E. Marchesi, L. Cleris, A. Donella-Deana, P. Drueckes, et al. (2008)
Haematologica 93, 653-661
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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 (2008)
Am. Assoc. Cancer Res. Educ. Book 2008, 589-599
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Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells.
J. Wu, F. Meng, H. Lu, L. Kong, W. Bornmann, Z. Peng, M. Talpaz, and N. J. Donato (2008)
Blood 111, 3821-3829
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Growth inhibition by STI571 in combination with radiation in human chronic myelogenous leukemia K562 cells.
F. Huguet, N. Giocanti, C. Hennequin, M. Croisy, E. Touboul, and V. Favaudon (2008)
Mol. Cancer Ther. 7, 398-406
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c-Met Inhibitors with Novel Binding Mode Show Activity against Several Hereditary Papillary Renal Cell Carcinoma-related Mutations.
S. F. Bellon, P. Kaplan-Lefko, Y. Yang, Y. Zhang, J. Moriguchi, K. Rex, C. W. Johnson, P. E. Rose, A. M. Long, A. B. O'Connor, et al. (2008)
J. Biol. Chem. 283, 2675-2683
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Concurrent Inhibition of Kit- and Fc{epsilon}RI-Mediated Signaling: Coordinated Suppression of Mast Cell Activation.
B. M. Jensen, M. A. Beaven, S. Iwaki, D. D. Metcalfe, and A. M. Gilfillan (2008)
J. Pharmacol. Exp. Ther. 324, 128-138
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Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond.
J. V. Melo and C. Chuah (2008)
Hematology 2008, 427-435
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Sorafenib Functions to Potently Suppress RET Tyrosine Kinase Activity by Direct Enzymatic Inhibition and Promoting RET Lysosomal Degradation Independent of Proteasomal Targeting.
I. Plaza-Menacho, L. Mologni, E. Sala, C. Gambacorti-Passerini, A. I. Magee, T. P. Links, R. M. W. Hofstra, D. Barford, and C. M. Isacke (2007)
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