Second Generation Inhibitors of BCR-ABL for the Treatment of Imatinib-Resistant Chronic Myeloid Leukaemia

Nat Rev Cancer. 2007 May;7(5):345-56. doi: 10.1038/nrc2126.

Abstract

Imatinib, a small-molecule ABL kinase inhibitor, is a highly effective therapy for early-phase chronic myeloid leukaemia (CML), which has constitutively active ABL kinase activity owing to the expression of the BCR-ABL fusion protein. However, there is a high relapse rate among advanced- and blast-crisis-phase patients owing to the development of mutations in the ABL kinase domain that cause drug resistance. Several second-generation ABL kinase inhibitors have been or are being developed for the treatment of imatinib-resistant CML. Here, we describe the mechanism of action of imatinib in CML, the structural basis of imatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Aurora Kinases
  • Benzamides
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Models, Biological
  • Models, Molecular
  • Mutation
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Pyrimidines / pharmacology*
  • Signal Transduction

Substances

  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases