Abstract
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-Abl inhibitors are able to overcome most imatinib-resistant mutants, with the exception of the frequent T315I 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 T315I substitution, but until now no crystal structure of the T315I Abl mutant has been solved. We show here the first crystal structure of the kinase domain of Abl T315I 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 T315I. The cocrystal structure of T315I 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.
Highlights
Imatinib, an ATP-competitive inhibitor that targets the tyrosine kinase activity of Bcr-Abl, is the first-line treatment for patients with chronic myelogenous leukemia (CML; ref. 1)
Diagnosed patients in chronic phase treated with imatinib generally achieve durable responses, whereas patients in advanced phases of CML frequently develop resistance to imatinib therapy, which is often due to the emergence of mutant forms of Bcr-Abl bearing point mutations in the kinase domain [1]
Imatinib binds and stabilizes an inactive conformation of the Abl kinase, in which the inhibitor interacts with the aromatic side chain of the conserved Phe of the Asp-Phe-Gly (DFG) motif, displacing the activation loop from its normal position and forcing it to adopt a substrate-like conformation, termed the ‘‘DFG-out’’ conformation [2]
Summary
An ATP-competitive inhibitor that targets the tyrosine kinase activity of Bcr-Abl, is the first-line treatment for patients with chronic myelogenous leukemia (CML; ref. 1). Mutations in the kinase domain of Abl that cause imatinib resistance either directly interfere with the inhibitor Two ATPcompetitive inhibitors that were designed to target the Aurora kinases and are in clinical development, MK-0457 (VX-680) and PHA-739358, have been reported to be active on T315I Abl mutant [9].
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