Flying Under the Radar: The New Wave of BCR-ABL Inhibitors

Nat Rev Drug Discov. 2007 Oct;6(10):834-48. doi: 10.1038/nrd2324.

Abstract

The introduction of the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec; Novartis) revolutionized the treatment of chronic myeloid leukaemia (CML). However, most patients with CML receiving imatinib still harbour molecular residual disease and some develop resistance associated with ABL kinase domain mutations. The second-generation BCR-ABL inhibitors nilotinib (Tasigna; Novartis) and dasatinib (Sprycel; Bristol-Myers Squibb) have shown significant activity after imatinib failure in clinical trials, but still face similar obstacles to imatinib, including negligible activity against the frequent BCR-ABL T315I mutation and modest effects in advanced phases of CML. Various medicinal chemistry efforts, in part aided by structural studies of the ABL kinase-imatinib complex have resulted in the synthesis of a new generation of BCR-ABL inhibitors, some of which have shown encouraging preliminary activity in clinical trials, including against T315I mutants. Here, we discuss these emerging therapies, which have the potential to improve the outcome of patients with CML.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Clinical Trials as Topic
  • Drug Design*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Fusion Proteins, bcr-abl
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Models, Molecular
  • Point Mutation
  • Protein Binding
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / genetics

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl