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[Cancer Research 62, 4236-4243, August 1, 2002]
© 2002 American Association for Cancer Research


Biochemistry and Biophysics

Crystal Structures of the Kinase Domain of c-Abl in Complex with the Small Molecule Inhibitors PD173955 and Imatinib (STI-571)1

Bhushan Nagar, William G. Bornmann, Patricia Pellicena, Thomas Schindler2, Darren R. Veach, W. Todd Miller, Bayard Clarkson and John Kuriyan3

Departments of Molecular and Cell Biology and Chemistry and Howard Hughes Medical Institute, University of California, Berkeley, California 94720 [B. N., P. P., J. K.]; Physical Biosciences Division, Lawrence Berkeley National Lab, Berkeley, California 94720 [B. N., P. P., J. K.]; Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [W. G. B., D. R. V., B. C.]; Laboratories of Molecular Biophysics, The Rockefeller University, New York, New York 10021 [T. S.]; and Department of Physiology and Biophysics, School of Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794 [W. T. M.]

The inadvertent fusion of the bcr gene with the abl gene results in a constitutively active tyrosine kinase (Bcr-Abl) that transforms cells and causes chronic myelogenous leukemia. Small molecule inhibitors of Bcr-Abl that bind to the kinase domain can be used to treat chronic myelogenous leukemia. We report crystal structures of the kinase domain of Abl in complex with two such inhibitors, imatinib (also known as STI-571 and Gleevec) and PD173955 (Parke-Davis). Both compounds bind to the canonical ATP-binding site of the kinase domain, but they do so in different ways. As shown previously in a crystal structure of Abl bound to a smaller variant of STI-571, STI-571 captures a specific inactive conformation of the activation loop of Abl in which the loop mimics bound peptide substrate. In contrast, PD173955 binds to a conformation of Abl in which the activation loop resembles that of an active kinase. The structure suggests that PD173955 would be insensitive to whether the conformation of the activation loop corresponds to active kinases or to that seen in the STI-571 complex. In vitro kinase assays confirm that this is the case and indicate that PD173955 is at least 10-fold more inhibitory than STI-571. The structures suggest that PD173955 achieves its greater potency over STI-571 by being able to target multiple forms of Abl (active or inactive), whereas STI-571 requires a specific inactive conformation of Abl.




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J. Biol. Chem., December 31, 2004; 279(53): 55827 - 55832.
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Mol. Cell. ProteomicsHome page
J. Wissing, K. Godl, D. Brehmer, S. Blencke, M. Weber, P. Habenberger, M. Stein-Gerlach, A. Missio, M. Cotten, S. Muller, et al.
Chemical Proteomic Analysis Reveals Alternative Modes of Action for Pyrido[2,3-d]pyrimidine Kinase Inhibitors
Mol. Cell. Proteomics, December 1, 2004; 3(12): 1181 - 1193.
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BloodHome page
T. O'Hare, R. Pollock, E. P. Stoffregen, J. A. Keats, O. M. Abdullah, E. M. Moseson, V. M. Rivera, H. Tang, C. A. Metcalf III, R. S. Bohacek, et al.
Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML
Blood, October 15, 2004; 104(8): 2532 - 2539.
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J. Biol. Chem.Home page
L. Jin, S. Pluskey, E. C. Petrella, S. M. Cantin, J. C. Gorga, M. J. Rynkiewicz, P. Pandey, J. E. Strickler, R. E. Babine, D. T. Weaver, et al.
The Three-dimensional Structure of the ZAP-70 Kinase Domain in Complex with Staurosporine: IMPLICATIONS FOR THE DESIGN OF SELECTIVE INHIBITORS
J. Biol. Chem., October 8, 2004; 279(41): 42818 - 42825.
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Mol. Biol. CellHome page
A. Swimm, B. Bommarius, Y. Li, D. Cheng, P. Reeves, M. Sherman, D. Veach, W. Bornmann, and D. Kalman
Enteropathogenic Escherichia coli Use Redundant Tyrosine Kinases to Form Actin Pedestals
Mol. Biol. Cell, August 1, 2004; 15(8): 3520 - 3529.
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J. Biol. Chem.Home page
C. D. Mol, D. R. Dougan, T. R. Schneider, R. J. Skene, M. L. Kraus, D. N. Scheibe, G. P. Snell, H. Zou, B.-C. Sang, and K. P. Wilson
Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase
J. Biol. Chem., July 23, 2004; 279(30): 31655 - 31663.
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ScienceHome page
N. P. Shah, C. Tran, F. Y. Lee, P. Chen, D. Norris, and C. L. Sawyers
Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
Science, July 16, 2004; 305(5682): 399 - 401.
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Clin. Chem.Home page
S. Soverini, G. Martinelli, M. Amabile, A. Poerio, M. Bianchini, G. Rosti, F. Pane, G. Saglio, and M. Baccarani
Denaturing-HPLC-Based Assay for Detection of ABL Mutations in Chronic Myeloid Leukemia Patients Resistant to Imatinib
Clin. Chem., July 1, 2004; 50(7): 1205 - 1213.
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S. Parmar, E. Katsoulidis, A. Verma, Y. Li, A. Sassano, L. Lal, B. Majchrzak, F. Ravandi, M. S. Tallman, E. N. Fish, et al.
Role of the p38 Mitogen-activated Protein Kinase Pathway in the Generation of the Effects of Imatinib Mesylate (STI571) in BCR-ABL-expressing Cells
J. Biol. Chem., June 11, 2004; 279(24): 25345 - 25352.
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J Biomol ScreenHome page
Z. Lu, Z. Yin, L. James, R. Syto, J. M. Stafford, S. Koseoglu, T. Mayhood, J. Myers, W. Windsor, P. Kirschmeier, et al.
Development of a Fluorescence Polarization Bead-Based Coupled Assay to Target Different Activity/Conformation States of a Protein Kinase
J Biomol Screen, June 1, 2004; 9(4): 309 - 321.
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ScienceHome page
M. E. M. Noble, J. A. Endicott, and L. N. Johnson
Protein Kinase Inhibitors: Insights into Drug Design from Structure
Science, March 19, 2004; 303(5665): 1800 - 1805.
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Genes Dev.Home page
C. L. Sawyers
Opportunities and challenges in the development of kinase inhibitor therapy for cancer
Genes & Dev., December 15, 2003; 17(24): 2998 - 3010.
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Proc. Natl. Acad. Sci. USAHome page
W. J. Netzer, F. Dou, D. Cai, D. Veach, S. Jean, Y. Li, W. G. Bornmann, B. Clarkson, H. Xu, and P. Greengard
Gleevec inhibits {beta}-amyloid production but not Notch cleavage
PNAS, October 14, 2003; 100(21): 12444 - 12449.
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Cancer Res.Home page
N. von Bubnoff, D. R. Veach, W. T. Miller, W. Li, J. Sanger, C. Peschel, W. G. Bornmann, B. Clarkson, and J. Duyster
Inhibition of Wild-Type and Mutant Bcr-Abl by Pyrido-Pyrimidine-Type Small Molecule Kinase Inhibitors
Cancer Res., October 1, 2003; 63(19): 6395 - 6404.
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Pharmacol. Rev.Home page
M. W. N. Deininger and B. J. Druker
Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib
Pharmacol. Rev., September 1, 2003; 55(3): 401 - 423.
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BloodHome page
S. Branford, Z. Rudzki, S. Walsh, I. Parkinson, A. Grigg, J. Szer, K. Taylor, R. Herrmann, J. F. Seymour, C. Arthur, et al.
Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis
Blood, July 1, 2003; 102(1): 276 - 283.
[Abstract] [Full Text] [PDF]


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Mol. Cell. Biol.Home page
K. Q. Tanis, D. Veach, H. S. Duewel, W. G. Bornmann, and A. J. Koleske
Two Distinct Phosphorylation Pathways Have Additive Effects on Abl Family Kinase Activation
Mol. Cell. Biol., June 1, 2003; 23(11): 3884 - 3896.
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BloodHome page
A. S. Corbin, P. L. Rosee, E. P. Stoffregen, B. J. Druker, and M. W. Deininger
Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib
Blood, June 1, 2003; 101(11): 4611 - 4614.
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E. A. Sausville
Is Another Bcr-Abl Inhibitor Needed for Chronic Myelogenous Leukemia?
Clin. Cancer Res., April 1, 2003; 9(4): 1233 - 1234.
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F. D. Bohmer, L. Karagyozov, A. Uecker, H. Serve, A. Botzki, S. Mahboobi, and S. Dove
A Single Amino Acid Exchange Inverts Susceptibility of Related Receptor Tyrosine Kinases for the ATP Site Inhibitor STI-571
J. Biol. Chem., February 7, 2003; 278(7): 5148 - 5155.
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BloodHome page
M. Warmuth, N. Simon, O. Mitina, R. Mathes, D. Fabbro, P. W. Manley, E. Buchdunger, K. Forster, I. Moarefi, and M. Hallek
Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases
Blood, January 15, 2003; 101(2): 664 - 672.
[Abstract] [Full Text] [PDF]


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ASH Education BookHome page
J. V. Melo, T. P. Hughes, and J. F. Apperley
Chronic Myeloid Leukemia
Hematology, January 1, 2003; 2003(1): 132 - 152.
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Cancer Res.Home page
P. La Rosee, A. S. Corbin, E. P. Stoffregen, M. W. Deininger, and B. J. Druker
Activity of the Bcr-Abl Kinase Inhibitor PD180970 against Clinically Relevant Bcr-Abl Isoforms That Cause Resistance to Imatinib Mesylate (Gleevec, STI571)
Cancer Res., December 15, 2002; 62(24): 7149 - 7153.
[Abstract] [Full Text] [PDF]


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D. Wisniewski, C. L. Lambek, C. Liu, A. Strife, D. R. Veach, B. Nagar, M. A. Young, T. Schindler, W. G. Bornmann, J. R. Bertino, et al.
Characterization of Potent Inhibitors of the Bcr-Abl and the c-Kit Receptor Tyrosine Kinases
Cancer Res., August 1, 2002; 62(15): 4244 - 4255.
[Abstract] [Full Text] [PDF]




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