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[Cancer Research 66, 1007-1014, January 15, 2006]
© 2006 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

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

Matthew A. Young1, Neil P. Shah3, Luke H. Chao1, Markus Seeliger1, Zdravko V. Milanov4, William H. Biggs, III4, Daniel K. Treiber4, Hitesh K. Patel4, Patrick P. Zarrinkar4, David J. Lockhart4, Charles L. Sawyers3 and John Kuriyan1,2

1 Departments of Molecular and Cell Biology and Chemistry, Howard Hughes Medical Institute, The University of California; 2 Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California; 3 Division of Hematology and Oncology, Department of Medicine, Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, California; and 4 Ambit Biosciences, San Diego, California

Requests for reprints: John Kuriyan, Department of Molecular and Cell Biology, University of California at Berkeley, Barker Hall MC 3202, Berkeley, CA 94720-3202. Phone: 510-643-0137; Fax: 510-643-0159; E-mail: kuriyan{at}uclink.berkeley.edu.

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)




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Copyright © 2006 by the American Association for Cancer Research.