Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia.
Bosutinib (SKI-606) is an orally active Src and Abl kinase inhibitor presently in Phase III trials for treatment of chronic myelogenous leukaemia (CML), and in Phase II trials for treatment of breast cancer. Bosutinib is a potent antiproliferative and proapoptotic agent in CML cells and inhibits Bcr-Abl mediated signalling at nanomolar concentrations. Short-term administration of bosutinib causes regression of K562 and KU812 CML tumour xenografts. BaF3 murine myeloid cells expressing wild-type Bcr-Abl are sensitive to bosutinib treatment, as are BaF3 cells expressing many imatinib-resistant forms of Bcr-Abl. Recent studies indicate that bosutinib is active against a broader spectrum of kinases than originally believed. These additional inhibitory activities have interesting possibilities for further clinical development. This review will focus on preclinical studies supporting the clinical development of bosutinib for treatment of CML, with a discussion on the broader potential of this agent in other oncology indications.
Boschelli
Frank
F
Department of Oncology, Wyeth Research (Wyeth Research is Now Pfizer Research), Pearl River, NY, USA. boschef@wyeth.com
Arndt
Kim
K
Gambacorti-Passerini
Carlo
C
D000814:Aniline Compounds / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D003497:Cyclic N-Oxides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000737:chemistry / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D019061:src-Family Kinases / Q000737:chemistry / Q000627:therapeutic use*
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; C014791:3-quinolinecarbonitrile N-oxide; D019061:src-Family Kinases