Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention AACR Conference on Molecular Diagnostics - 2008
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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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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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