AMN107, a novel aminopyrimidine inhibitor of p190 Bcr‐Abl activation and of in vitro proliferation of Philadelphia‐positive acute lymphoblastic leukemia cells

• Published in: Cancer 2005-09, Vol.104 (6), p.1230-1236
• Main Authors: Verstovsek, Srdan, Golemovic, Mirna, Kantarjian, Hagop, Manshouri, Tashi, Estrov, Zeev, Manley, Paul, Sun, Tong, Arlinghaus, Ralph B., Alland, Leila, Dugan, Margaret, Cortes, Jorge, Giles, Francis, Beran, Miloslav
• Format: Article
• Language: English
• Subjects: acute lymphoblastic leukemia; AMN107; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Bcr‐Abl kinase inhibitor; Benzamides; Biological and medical sciences; Caspase 3; Caspases - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chromosome aberrations; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - metabolism; Humans; imatinib; Imatinib Mesylate; in vitro models; Medical genetics; Medical sciences; Phosphorylation; Piperazines - pharmacology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Pyrimidines - pharmacology; Tumors
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.21299

BACKGROUND Previous studies have shown that patients with Bcr‐Abl–positive acute lymphoblastic leukemia (ALL) either have primary disease that is refractory to imatinib mesylate or develop disease recurrence after an initial response. METHODS The authors investigated the effects of a newly designed Bcr‐Abl inhibitor, AMN107, by comparing its in vitro inhibitory potency on p190 Bcr‐Abl ALL cell lines with that of imatinib. RESULTS In two Philadelphia (Ph)‐positive ALL cell lines, AMN107 was found to be 30–40 times more potent than imatinib in inhibiting cellular proliferation. AMN107 was also more effective than imatinib in inhibiting phosphorylation of p190 Bcr‐Abl tyrosine kinase in cell lines and primary ALL cells. The inhibition of cellular proliferation was associated with the induction of apoptosis in only one of the cell lines. No activity was observed in cell lines lacking the BCR‐ABL genotype. CONCLUSIONS The results of the current study suggest the superior potency of AMN107 compared with imatinib in Ph‐positive ALL and support clinical trials of AMN107 in patients with Ph‐positive ALL. Cancer 2005. © 2005 American Cancer Society. AMN107 is highly effective in inhibiting the activation of p190 Bcr‐Abl and the in vitro proliferation of p190 Bcr‐Abl–expressing acute lymphoblastic leukemia cells. With a similar mechanism of action, the antiproliferative potency of AMN107 was 30–40‐fold higher than that of imatinib.