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

JS Tokarski, JA Newitt, CYJ Chang, JD Cheng… - Cancer research, 2006 - AACR
JS Tokarski, JA Newitt, CYJ Chang, JD Cheng, M Wittekind, SE Kiefer, K Kish, FYF Lee…
Cancer research, 2006AACR
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 …
Abstract
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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