title: Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680.
abstract: We present a high-resolution (2.0 A) crystal structure of the catalytic domain of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is resistant to the Abl inhibitor imatinib. The structure is determined in complex with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge, MA), which blocks the activity of various imatinib-resistant mutant forms of Abl, including one (T315I) that is resistant to both imatinib and BMS-354825 (dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective against all other imatinib-resistant forms of BCR-Abl. VX-680 is shown to have significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples. The Abl kinase domain bound to VX-680 is not phosphorylated on the activation loop in the crystal structure but is nevertheless in an active conformation, previously unobserved for Abl and inconsistent with the binding of imatinib. The adoption of an active conformation is most likely the result of synergy between the His(396)Pro mutation, which destabilizes the inactive conformation required for imatinib binding, and the binding of VX-680, which favors the active conformation through hydrogen bonding and steric effects. VX-680 is bound to Abl in a mode that accommodates the substitution of isoleucine for threonine at residue 315 (the "gatekeeper" position). The avoidance of the innermost cavity of the Abl kinase domain by VX-680 and the specific recognition of the active conformation explain the effectiveness of this compound against mutant forms of BCR-Abl, including those with mutations at the gatekeeper position.
authors.affiliation: Departments of Molecular and Cell Biology and Chemistry, Howard Hughes Medical Institute, The University of California at Berkeley, Berkeley, CA 94720, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Young
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.forename: Luke H
authors.initials: LH
authors.lastname: Chao
authors.forename: Markus
authors.initials: M
authors.lastname: Seeliger
authors.forename: Zdravko V
authors.initials: ZV
authors.lastname: Milanov
authors.forename: William H
authors.initials: WH
authors.lastname: Biggs
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Treiber
authors.forename: Hitesh K
authors.initials: HK
authors.lastname: Patel
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Zarrinkar
authors.forename: David J
authors.initials: DJ
authors.lastname: Lockhart
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D064127:Aurora Kinases; D001549:Benzamides; D020134:Catalytic Domain; D003461:Crystallography; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D004926:Escherichia coli / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D016313:Genes, abl; D006801:Humans; D006860:Hydrogen Bonding; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D003521:Cyclopropanes; D011720:Pyrazoles
chemical_list: D064127:Aurora Kinases; D001549:Benzamides; D000069439:Dasatinib; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D016315:Proto-Oncogene Proteins c-abl; D011743:Pyrimidines; D013844:Thiazoles; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles