Crystal Structure of the T315I Mutant of Abl Kinase

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Abstract
Imatinib (Gleevec) is currently the frontline therapy for chronic myeloid leukemia (CML), a disease characterized by the presence of a constitutively activated chimeric tyrosine kinase protein Bcr‐Abl. However, drug resistance often occurs at later stages of the disease, principally because of the occurrence of mutations in the kinase domain. Second generation Bcr‐Abl inhibitors, such as dasatinib and nilotinib are capable of inhibiting many imatinib‐resistant forms of the kinase but not the form in which threonine is mutated to isoleucine at the gatekeeper position (T315I). In this study, we present the crystal structure of the kinase domain of the c‐Abl T315I mutant, as well as the wild‐type form, in complex with a pyrrolopyridine inhibitor, PPY‐A. The side chain of Ile315 is accommodated in the Abl T315I mutant structure without large conformational changes proximal to the site of mutation. In contrast to other inhibitors, such as imatinib and dasatinib, PPY‐A does not occupy the hydrophobic pocket behind the gatekeeper residue. This binding mode, coupled with augmented contacts with the glycine‐rich loop, appears to be critical for its ability to override the T315I mutation. The data presented here may provide structural guidance for the design of clinically useful inhibitors of Bcr‐Abl T315I.