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

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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				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. [Abstract] [Full Text] [PDF]

				C. L. Sawyers Opportunities and challenges in the development of kinase inhibitor therapy for cancer Genes & Dev., December 15, 2003; 17(24): 2998 - 3010. [Full Text] [PDF]

				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. [Abstract] [Full Text] [PDF]

				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. [Abstract] [Full Text] [PDF]

				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. [Abstract] [Full Text] [PDF]

				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]

				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. [Abstract] [Full Text] [PDF]

				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. [Abstract] [Full Text] [PDF]

				E. A. Sausville Is Another Bcr-Abl Inhibitor Needed for Chronic Myelogenous Leukemia? Clin. Cancer Res., April 1, 2003; 9(4): 1233 - 1234. [Full Text] [PDF]

				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. [Abstract] [Full Text] [PDF]

				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]

				J. V. Melo, T. P. Hughes, and J. F. Apperley Chronic Myeloid Leukemia Hematology, January 1, 2003; 2003(1): 132 - 152. [Abstract] [Full Text] [PDF]

				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]

				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]