The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants

被引:533
作者
Tokarski, John S. [1 ]
Newitt, John A. [1 ]
Chang, Chieh Ying J. [1 ]
Cheng, Janet D. [1 ]
Wittekind, Michael [1 ]
Kiefer, Susan E. [1 ]
Kish, Kevin [1 ]
Lee, Francis Y. F. [1 ]
Borzillerri, Robert [1 ]
Lombardo, Louis J. [1 ]
Xie, Dianlin [1 ]
Zhang, Yaqun [1 ]
Klei, Herbert E. [1 ]
机构
[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Struct Biol & Modeling, Princeton, NJ 08543 USA
关键词
D O I
10.1158/0008-5472.CAN-05-4187
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:5790 / 5797
页数:8
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