Bosutinib.

TY - JOUR

T1 - Bosutinib.

AU - von Amsberg, Gunhild

AU - Schafhausen, Philippe

AU - Brümmendorf, Tim

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

KW - Animals

KW - Humans

KW - Clinical Trials as Topic

KW - inhibitors

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy

KW - Neoplasms drug therapy

KW - Aniline Compounds pharmacology

KW - Fusion Proteins, bcr-abl antagonists

KW - Nitriles pharmacology

KW - Oncogene Proteins v-abl antagonists

KW - Protein Kinase Inhibitors therapeutic use

KW - Quinolines pharmacology

KW - Animals

KW - Humans

KW - Clinical Trials as Topic

KW - inhibitors

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy

KW - Neoplasms drug therapy

KW - Aniline Compounds pharmacology

KW - Fusion Proteins, bcr-abl antagonists

KW - Nitriles pharmacology

KW - Oncogene Proteins v-abl antagonists

KW - Protein Kinase Inhibitors therapeutic use

KW - Quinolines pharmacology

M3 - SCORING: Zeitschriftenaufsatz

VL - 184

SP - 119

EP - 127

JO - Recent Results Cancer Res

JF - Recent Results Cancer Res

SN - 0080-0015

ER -