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Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase
Thomas Schindler,1William Bornmann,3Patricia Pellicena,4W. Todd Miller,4Bayard Clarkson,3John Kuriyan12*
The inadvertent activation of the Abelson tyrosine kinase (Abl)
causes chronic myelogenous leukemia (CML). A small-moleculeinhibitor
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 ofSTI-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 activeprotein
kinases, as well as in the inactive form of the closelyrelated Src
kinases. These results suggest that compounds thatexploit the
distinctive inactivation mechanisms of individualprotein 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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ABL Mutations in Late Chronic Phase Chronic Myeloid Leukemia Patients With Up-Front Cytogenetic Resistance to Imatinib Are Associated With a Greater Likelihood of Progression to Blast Crisis and Shorter Survival: A Study by the GIMEMA Working Party on Chronic Myeloid Leukemia.
S. Soverini, G. Martinelli, G. Rosti, S. Bassi, M. Amabile, A. Poerio, B. Giannini, E. Trabacchi, F. Castagnetti, N. Testoni, et al. (2005)
J. Clin. Oncol.
23, 4100-4109
|Abstract »|Full Text »|PDF »
In vitro Activity of Bcr-Abl Inhibitors AMN107 and BMS-354825 against Clinically Relevant Imatinib-Resistant Abl Kinase Domain Mutants.
T. O'Hare, D. K. Walters, E. P. Stoffregen, T. Jia, P. W. Manley, J. Mestan, S. W. Cowan-Jacob, F. Y. Lee, M. C. Heinrich, M. W.N. Deininger, et al. (2005)
Cancer Res.
65, 4500-4505
|Abstract »|Full Text »|PDF »
PD166326, a novel tyrosine kinase inhibitor, has greater antileukemic activity than imatinib mesylate in a murine model of chronic myeloid leukemia.
N. C. Wolff, D. R. Veach, W. P. Tong, W. G. Bornmann, B. Clarkson, and R. L. Ilaria Jr (2005)
Blood
105, 3995-4003
|Abstract »|Full Text »|PDF »
Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance.
P.-H. Tseng, H.-P. Lin, J. Zhu, K.-F. Chen, E. M. Hade, D. C. Young, J. C. Byrd, M. Grever, K. Johnson, B. J. Druker, et al. (2005)
Blood
105, 4021-4027
|Abstract »|Full Text »|PDF »
Chemical Theory and Computation Special Feature: Molecular dynamics and protein function.
Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner.
R. Seggewiss, K. Lore, E. Greiner, M. K. Magnusson, D. A. Price, D. C. Douek, C. E. Dunbar, and A. Wiestner (2005)
Blood
105, 2473-2479
|Abstract »|Full Text »|PDF »
Label-free detection of small-molecule-protein interactions by using nanowire nanosensors.
W. U. Wang, C. Chen, K.-h. Lin, Y. Fang, and C. M. Lieber (2005)
PNAS
102, 3208-3212
|Abstract »|Full Text »|PDF »
Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance.
M. R. Burgess, B. J. Skaggs, N. P. Shah, F. Y. Lee, and C. L. Sawyers (2005)
PNAS
102, 3395-3400
|Abstract »|Full Text »|PDF »
Chronic Myeloid Leukemia: Current Application of Cytogenetics and Molecular Testing for Diagnosis and Treatment.
A. Tefferi, G. W. Dewald, M. L. Litzow, J. Cortes, M. J. Mauro, M. Talpaz, and H. M. Kantarjian (2005)
Mayo Clin. Proc.
80, 390-402
|Abstract »|PDF »
Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment.
S. Chu, H. Xu, N. P. Shah, D. S. Snyder, S. J. Forman, C. L. Sawyers, and R. Bhatia (2005)
Blood
105, 2093-2098
|Abstract »|Full Text »|PDF »
A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies the mutation pattern for PD166326, an alternative Abl kinase inhibitor.
N. von Bubnoff, D. R. Veach, H. van der Kuip, W. E. Aulitzky, J. Sanger, P. Seipel, W. G. Bornmann, C. Peschel, B. Clarkson, and J. Duyster (2005)
Blood
105, 1652-1659
|Abstract »|Full Text »|PDF »
