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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Benzamides
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Bone Marrow Cells / cytology
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Cell Line
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Cell Line, Tumor
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Cell Survival
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm
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Fusion Proteins, bcr-abl / antagonists & inhibitors*
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Fusion Proteins, bcr-abl / genetics*
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Hematopoietic Stem Cells / cytology
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Imatinib Mesylate
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Inhibitory Concentration 50
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Mice
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Models, Biological
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Models, Chemical
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Mutation
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Mycoplasma / metabolism
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Phosphorylation
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Piperazines / pharmacology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology*
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Retroviridae / genetics
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Time Factors
Substances
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Antineoplastic Agents
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Benzamides
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Piperazines
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Pyrimidines
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Imatinib Mesylate
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Fusion Proteins, bcr-abl
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nilotinib