Crystal Structure Of The T315l Abl Mutant In Complex With The Aurora Kinases Inhibitor Pha-739358

Mutations in the kinase domain of Bcr-Abl are the most common cause of resistance to therapy with imatinib in patients with chronic myelogenous leukemia (CML). Second-generation Bcr-AbI inhibitors are able to overcome most imatinib-resistant mutants, with the exception of the frequent T3151 substitution, which is emerging as a major cause of resistance to these drugs in CML patients. Structural studies could be used to support the drug design process for the development of inhibitors able to target the T3151 substitution, but until now no crvstal structure of the T3151 Abl mutant has been solved. We show here the first crystal structure of the kinase domain of Abl T3151 in complex with PHA-739358, an Aurora kinase inhibitor currently in clinical development for solid and hematologic malignancies. This compound inhibits in vitro the kinase activity of wild-type Abl and of several mutants, including T3151. The cocrystal structure of T3151 Abl kinase domain provides the structural basis for this activity: the inhibitor associates with an active conformation of the kinase domain in the ATP-binding pocket and lacks the steric hindrance imposed by the substitution of threonine by isoleucine.