Bosutinib

Recent Results Cancer Res. 2010:184:119-27. doi: 10.1007/978-3-642-01222-8_9.

Abstract

Bosutinib (SKI-606) is a 7-alkoxy-3-quinolinecarbonitrile, which functions as a dual inhibitor of Src and Abl kinases. In biochemical and proliferation assays, the compound was shown to be active against src family kinases and Bcr-Abl at IC50s of 100 and 90 nM, respectively. The bcr-abl fusion gene product, a consecutively activated tyrosine kinase, which is crucial for the development of chronic myeloid leukaemia (CML), is highly sensitive to bosutinib. Interestingly, distinctly lower concentrations of the dual src/abl inhibitor are required to ablate Bcr-Abl phosphorylation when compared to first-generation tyrosine kinase inhibitor imatinib (IM). Bosutinib is a potent inhibitor of CML cell proliferation in vitro and in vivo experiments and has demonstrated promising harbouring results in CML patients resistance or intolerance to IM in ongoing phase I/II clinical trials. Remarkably, bosutinib has been found to be capable of overcoming the majority of IM-resistant bcr-abl mutations. A randomised open label phase III clinical study to compare the efficacy of bosutinib and IM in first-line therapy of Ph+ chronic phase (CP) CML has recently been initiated. In a phase I/II clinical study with subjects suffering from advanced stages of solid tumours, long-term responses have also been reported. In conclusion, Bosutinib is a promising novel small molecule inhibitor for targeted therapy of CML and solid tumours.

Publication types

  • Review

MeSH terms

  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use*
  • Animals
  • Clinical Trials as Topic
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Neoplasms / drug therapy*
  • Nitriles / pharmacology
  • Nitriles / therapeutic use*
  • Oncogene Proteins v-abl / antagonists & inhibitors
  • Protein Kinase Inhibitors / therapeutic use*
  • Quinolines / pharmacology
  • Quinolines / therapeutic use*

Substances

  • Aniline Compounds
  • Nitriles
  • Oncogene Proteins v-abl
  • Protein Kinase Inhibitors
  • Quinolines
  • bosutinib
  • Fusion Proteins, bcr-abl