Crystal structure of the T315I Abl mutant in complex with the Aurora kinases inhibitor PHA-739358

Michele Modugno, Elena Casale, Chiara Soncini, Pamela Rosettani, Riccardo Colombo, Rosita Lupi, Luisa Rusconi, Daniele Fancelli, Patrizia Carpinelli, Alexander D. Cameron, Antonella Isacchi, Jürgen Moll

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)7987-7990
Number of pages4
JournalCancer Research
Volume67
Issue number17
DOIs
Publication statusPublished - Sep 1 2007

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Modugno, M., Casale, E., Soncini, C., Rosettani, P., Colombo, R., Lupi, R., Rusconi, L., Fancelli, D., Carpinelli, P., Cameron, A. D., Isacchi, A., & Moll, J. (2007). Crystal structure of the T315I Abl mutant in complex with the Aurora kinases inhibitor PHA-739358. Cancer Research, 67(17), 7987-7990. https://doi.org/10.1158/0008-5472.CAN-07-1825