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

Ellen Weisberg; Paul W. Manley; Werner Breitenstein; Josef Brüggen; Sandra W. Cowan‐Jacob; Arghya Ray; Brian J.P. Huntly; Doriano Fabbro; Gabriele Fendrich; Elizabeth Hall–Meyers; Andrew L. Kung; Jürgen Mestan; George Q. Daley; Linda M. Callahan; Laurie Catley; Cara Cavazza; Mohammed Azam; Donna Neuberg; Renee D. Wright; D. Gary Gilliland; James D. Griffin

doi:10.1016/j.ccr.2005.01.007

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.

Keywords

MutantCancer researchMutationChemistryCell biologyBiologyBiochemistryGene

MeSH Terms

AnimalsAntineoplastic AgentsBenzamidesBone Marrow CellsCell LineCell LineTumorCell SurvivalCrystallographyX-RayDose-Response RelationshipDrugDrug ResistanceNeoplasmFusion Proteinsbcr-ablHematopoietic Stem CellsImatinib MesylateInhibitory Concentration 50LeukemiaMyelogenousChronicBCR-ABL PositiveMiceModelsBiologicalModelsChemicalMutationMycoplasmaPhosphorylationPiperazinesPrecursor Cell Lymphoblastic Leukemia-LymphomaPyrimidinesRetroviridaeTime Factors

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Publication Info

Year: 2005
Type: article
Volume: 7
Issue: 2
Pages: 129-141
Citations: 1470
Access: Closed

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APA Style

                            
                                
                                    Ellen Weisberg, 
                                
                                    Paul W. Manley, 
                                
                                    Werner Breitenstein
                                
                                et al.
                            
                            (2005). 
                            Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. 
                            Cancer Cell
                            , 7
                            (2)
                            , 129-141.
                            https://doi.org/10.1016/j.ccr.2005.01.007
                        

Identifiers

DOI: 10.1016/j.ccr.2005.01.007
PMID: 15710326

Data Quality

Data completeness: 86%