engleski

AMN107, a Novel Aminopyrimidine Inhibitor of Bcr-Abl, Has In Vitro Activity Against Imatinib-Resistant Chronic Myeloid Leukemia

Resistance to or intolerance of imatinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared to those of imatinib, on imatinib-sensitive (KBM5 and KBM7) and -resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0). Compared to the anti-proliferative activity of imatinib, AMN107 was 43-times more potent in KBM5 (IC50 of 11.3 versus 480.5 nM) and 60-times more potent in KBM7 (IC50 of 4.3 versus 259.0 nM) cells. IC50 for AMN107 and imatinib were 2418.3 and 6361.4 nM, respectively, in KBM5-STI571R1.0, and 97.2 and 2497.3 nM, respectively, in KBM7-STI571R1.0 cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient (SCID) mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/day AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, as compared to controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.

Philadelphia chromosome; chronic myeloid leukemia; imatinib; AMN107; kinase inhibitor; resistance

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