title: The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants.
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.
authors.affiliation: Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Princeton, New Jersey, USA. john.tokarski@bms.com
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: John A
authors.initials: JA
authors.lastname: Newitt
authors.forename: Chieh Ying J
authors.initials: CY
authors.lastname: Chang
authors.forename: Janet D
authors.initials: JD
authors.lastname: Cheng
authors.forename: Michael
authors.initials: M
authors.lastname: Wittekind
authors.forename: Susan E
authors.initials: SE
authors.lastname: Kiefer
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
authors.forename: Francis Y F
authors.initials: FY
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Borzillerri
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Dianlin
authors.initials: D
authors.lastname: Xie
authors.forename: Yaqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Klei
mesh_terms: 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
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D000069439:Dasatinib