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.

Keywords::

• BCR–ABL
• bosutinib
• CML
• dasatinib
• imatinib
• nilotinib
• point mutation
• SRC
• SRC/ABL kinase inhibitor
• tyrosine kinase

Financial & competing interests disclosure

Gunhild Keller, Philippe Schafhausen and Tim Brümmendorf have participated in clinical trials using Bosutinib. Tim Brümmendorf served as a consultant for Wyeth and received travel support for participation in study-related meetings and presentation of study data at scientific meetings. Tim Brümmendorf holds research grants by Novartis and Bristol Myers Squibb and serves as consultant and speaker receiving honoraria from both companies. Philippe Schafhausen serves as a consultant and speaker receiving honoraria from Bristol Myers Squibb. Gunhild Keller has received travel support by Bristol Myers Squibb and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.