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

来源：

CANCER RESEARCH | 2006年 / 66卷 / 11期

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

页码：5790 / 5797

页数：8

共 44 条

[1] Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL [J].