In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants

Imatinib, a Bcr-Ab1 tyrosine kinase inhibitor, is a highly effective therapy for patients with chronic myelogenous leukemia (CML). Despite durable responses in most chronic phase patients, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired imatinib resistance has been traced to Bcr-Ab1 kinase domain mutations with decreased imatinib sensitivity. Thus, alternate Bcr-Ab1 kinase inhibitors that have activity against imatinib-resistant mutants would be useful for patients who relapse on imatinib therapy. Two such Bcr-Ab1 inhibitors are currently being evaluated in clinical trials: the improved potency, selective Ab1 inhibitor AMN107 and the highly potent dual Src/Ab1 inhibitor BMS-354825. In the current article, we compared imatinib, AMN107, and BMS354825 in cellular and biochemical assays against a panel of 16 kinase domain mutants representing > 90% of clinical isolates. We report that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wildtype Bcr-Ab1 and that similar improvements are maintained for all imatinib-resistant mutants tested, with the exception of T315I. Thus, both inhibitors hold promise for treating imatinib-refractory CML.