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Equally Potent Inhibition of c-Src and Abl by Compounds that Recognize Inactive Kinase Conformations

¹ Howard Hughes Medical Institute and ² Department of Molecular and Cell Biology and Department of Chemistry, University of California; ³ Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California; ⁴ Department of Chemistry, University of Washington, Seattle, Washington; ⁵ Division of Hematology/Oncology, Department of Medicine, University of California-San Francisco School of Medicine, San Francisco, California; and ⁶ D. E. Shaw Research; ⁷ Center for Computational Biology and Bioinformatics, Columbia University, New York, New York

Requests for reprints: Dustin Maly, University of Washington, Box 351700, Seattle, WA 98195. Phone: 206-543-1653. E-mail: maly{at}chem.washington.edu or John Kuriyan, University of California, Berkeley, 176 Stanley Hall, QB3, Berkeley, CA 94720-3220 Phone: 510-643-0137; Fax: 510-643-2352; E-mail: kuriyan{at}berkeley.edu.

Key Words: leukemia • Abl • imatinib • resistance mutations • structure

Imatinib is an inhibitor of the Abl tyrosine kinase domain that is effective in the treatment of chronic myelogenic leukemia. Although imatinib binds tightly to the Abl kinase domain, its affinity for the closely related kinase domain of c-Src is at least 2,000-fold lower. Imatinib recognition requires a specific inactive conformation of the kinase domain, in which a conserved Asp-Phe-Gly (DFG) motif is flipped with respect to the active conformation. The inability of c-Src to readily adopt this flipped DFG conformation was thought to underlie the selectivity of imatinib for Abl over c-Src. Here, we present a series of inhibitors (DSA compounds) that are based on the core scaffold of imatinib but which bind with equally high potency to c-Src and Abl. The DSA compounds bind to c-Src in the DFG-flipped conformation, as confirmed by crystal structures and kinetic analysis. The origin of the high affinity of these compounds for c-Src is suggested by the fact that they also inhibit clinically relevant Abl variants bearing mutations in a structural element, the P-loop, that normally interacts with the phosphate groups of ATP but is folded over a substructure of imatinib in Abl. Importantly, several of the DSA compounds block the growth of Ba/F3 cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile "gatekeeper" mutation, but do not suppress the growth of parental Ba/F3 cells. [Cancer Res 2009;69(6):2384–92