Imatinib is the current first-line therapy for patients with chronic myeloid leukemia. The most prevalent mechanism of relapse on imatinib therapy involves specific mutations in the kinase domain of Bcr-Abl that interfere with imatinib binding without eliminating kinase activity. Two new Bcr-Abl inhibitors are in clinical development: the improved potency Abl inhibitor AMN107 and the highly potent Src/Abl inhibitor BMS-354825. In this study, imatinib, AMN107, and BMS-354825 were compared in cellular and biochemical assays using a panel of kinase domain mutants representing >90% of clinical isolates. AMN107 and BMS-354825 were significantly more potent than imatinib against cells expressing Bcr-Abl and similar improvements were maintained for all imatinib-resistant Bcr-Abl mutants tested, with the exception of T315I. AMN107, like imatinib, interacts with the inactive conformation of Abl. However, AMN107 binds more tightly than imatinib and, as a consequence, is capable of inhibiting most imatinib-resistant mutants. The schematic diagram shows AMN107 (tube representation with a transparent yellow surface) as bound in a crystal structure of M351T Abl kinase (light blue). The locations of residues on Abl kinase corresponding to imatinibresistant mutant forms of Bcr-Abl detected in patients. The residues are color coded according to their sensitivity to inhibition by AMN107. Mutations of residues shaded in red are highly sensitive to AMN107, residues in orange show medium sensitivity, residues in green show low sensitivity, and the blue residue (T315I) is insensitive to AMN107. Both of these potent new Bcr-Abl inhibitors hold promise for treating imatinib-refractory CML. For details, see the article by O'Hare et al. on page 4500 of this issue.