title: Bosutinib: a dual SRC/ABL kinase inhibitor for the treatment of chronic myeloid leukemia.
abstract: The tyrosine kinase inhibitor imatinib mesylate (IM) set new standards in the treatment of chronic myeloid leukemia (CML). However, emergence of resistance to IM became a major therapeutic challenge. Bosutinib (SKI-606), a 7-alkoxy-3-quinolinecarbonitrile, functions as a dual inhibitor of SRC and ABL kinases, and preclinical studies demonstrated a high antiproliferative activity in human and murine CML cell lines. In ongoing Phase I/II clinical trials, bosutinib yielded promising results revealing high clinical efficacy, good tolerability and reduced toxicity in IM-resistant or -intolerant CML patients. In this article, we provide an overview on the mechanism of action, and the preclinical and currently available clinical data for bosutinib. Owing to its favorable toxicity profile and its high antileukemic activity, bosutinib is a promising novel treatment option for patients with CML. A recently initiated, randomized open-label Phase III clinical study will clarify its role in first-line therapy of Philadelphia chromosome-positive chronic-phase CML.
authors.affiliation: Klinik für Hämatologie und Onkologie mit der Sektion Pneumologie, Universitäres Cancer Center Hamburg (UCCH), Universitäts-Klinikum Hamburg-Eppendorf, Martinistraße 52, Hamburg, Germany. g.keller@uke.uni-hamburg.de
authors.forename: Gunhild
authors.initials: G
authors.lastname: Keller
authors.forename: Philippe
authors.initials: P
authors.lastname: Schafhausen
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brummendorf
mesh_terms: D000814:Aniline Compounds / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D009570:Nitriles / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases