The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants.
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.
Tokarski
John S
JS
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Princeton, New Jersey, USA. john.tokarski@bms.com
Newitt
John A
JA
Chang
Chieh Ying J
CY
Cheng
Janet D
JD
Wittekind
Michael
M
Kiefer
Susan E
SE
Kish
Kevin
K
Lee
Francis Y F
FY
Borzillerri
Robert
R
Lombardo
Louis J
LJ
Xie
Dianlin
D
Zhang
Yaqun
Y
Klei
Herbert E
HE
D000818:Animals; D001549:Benzamides; D018360:Crystallography, X-Ray; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D000069439:Dasatinib