2GQG

X-ray Crystal Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain

Summary for 2GQG

• Entry DOI: 10.2210/pdb2gqg/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase ABL1, N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton. Isoform IB: Nucleus membrane; Lipid-anchor: P00519
• Total number of polymer chains: 2
• Total formula weight: 65503.58

Authors

Klei, H.E. (deposition date: 2006-04-20, release date: 2006-11-21, Last modification date: 2024-11-20)

Primary citation

Tokarski, J.S.,Newitt, J.,Chang, C.Y.J.,Cheng, J.D.,Wittekind, M.,Kiefer, S.E.,Kish, K.,Lee, F.Y.F.,Borzilerri, R.,Lombardo, L.J.,Xie, D.,Zhang, Y.,Klei, H.E.
The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants
CANCER RES., 66:5790-5797, 2006

PubMed 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.

PubMed: 16740718
DOI: 10.1158/0008-5472.CAN-05-4187

Experimental method

X-RAY DIFFRACTION (2.4 Å)