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Cancer Cell. 2005 Feb;7(2):129-41.

Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl.

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  • 1Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Erratum in

  • Cancer Cell. 2005 Apr;7(4):399. Mohammed, Azam [corrected to Azam, Mohammad].

Abstract

The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 <30 nM), which is significantly more potent than imatinib, and active against a number of imatinib-resistant Bcr-Abl mutants. Crystallographic analysis of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL.

PMID:
15710326
[PubMed - indexed for MEDLINE]
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