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

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

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzamides
  • Bone Marrow Cells / cytology
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics*
  • Hematopoietic Stem Cells / cytology
  • Imatinib Mesylate
  • Inhibitory Concentration 50
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Mice
  • Models, Biological
  • Models, Chemical
  • Mutation
  • Mycoplasma / metabolism
  • Phosphorylation
  • Piperazines / pharmacology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Retroviridae / genetics
  • Time Factors

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl