Structure of the Kinase Domain of an Imatinib-Resistant Abl Mutant in Complex with the Aurora Kinase Inhibitor VX-680

  • Matthew A. Young
    1Departments of Molecular and Cell Biology and Chemistry, Howard Hughes Medical Institute, The University of California;
  • Neil P. Shah
    3Division of Hematology and Oncology, Department of Medicine, Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, California; and
  • Luke H. Chao
    1Departments of Molecular and Cell Biology and Chemistry, Howard Hughes Medical Institute, The University of California;
  • Markus Seeliger
    1Departments of Molecular and Cell Biology and Chemistry, Howard Hughes Medical Institute, The University of California;
  • Zdravko V. Milanov
    4Ambit Biosciences, San Diego, California
  • William H. Biggs
    4Ambit Biosciences, San Diego, California
  • Daniel K. Treiber
    4Ambit Biosciences, San Diego, California
  • Hitesh K. Patel
    4Ambit Biosciences, San Diego, California
  • Patrick P. Zarrinkar
    4Ambit Biosciences, San Diego, California
  • David J. Lockhart
    4Ambit Biosciences, San Diego, California
  • Charles L. Sawyers
    3Division of Hematology and Oncology, Department of Medicine, Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, California; and
  • John Kuriyan
    1Departments of Molecular and Cell Biology and Chemistry, Howard Hughes Medical Institute, The University of California;

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<jats:title>Abstract</jats:title> <jats:p>We present a high-resolution (2.0 Å) 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 His396Pro 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. (Cancer Res 2006; 66(2): 1007-14)</jats:p>

収録刊行物

  • Cancer Research

    Cancer Research 66 (2), 1007-1014, 2006-01-15

    American Association for Cancer Research (AACR)

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