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[Cancer Research 66, 5790-5797, June 1, 2006]
© 2006 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants

John S. Tokarski, John A. Newitt, Chieh Ying J. Chang, Janet D. Cheng, Michael Wittekind, Susan E. Kiefer, Kevin Kish, Francis Y.F. Lee, Robert Borzillerri, Louis J. Lombardo, Dianlin Xie, Yaqun Zhang and Herbert E. Klei

Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Princeton, New Jersey

Requests for reprints: John S. Tokarski, Department of Structural Biology and Modeling, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543. Phone: 609-252-6154; Fax: 609-252-6030; E-mail: john.tokarski{at}bms.com.

Chronic myeloid leukemia (CML) is caused by the constitutively activated tyrosine kinase breakpoint cluster (BCR)-ABL. Current frontline therapy for CML is imatinib, an inhibitor of BCR-ABL. Although imatinib has a high rate of clinical success in early phase CML, treatment resistance is problematic, particularly in later stages of the disease, and is frequently mediated by mutations in BCR-ABL. Dasatinib (BMS-354825) is a multitargeted tyrosine kinase inhibitor that targets oncogenic pathways and is a more potent inhibitor than imatinib against wild-type BCR-ABL. It has also shown preclinical activity against all but one of the imatinib-resistant BCR-ABL mutants tested to date. Analysis of the crystal structure of dasatinib-bound ABL kinase suggests that the increased binding affinity of dasatinib over imatinib is at least partially due to its ability to recognize multiple states of BCR-ABL. The structure also provides an explanation for the activity of dasatinib against imatinib-resistant BCR-ABL mutants. (Cancer Res 2006; 66(11): 5790-7)




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