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

  1. Srdan Verstovsek M.D.1,
  2. Mirna Golemovic M.D.1,
  3. Hagop Kantarjian M.D.1,
  4. Tashi Manshouri M.D.1,
  5. Zeev Estrov M.D.1,
  6. Paul Manley Ph.D.2,†,
  7. Tong Sun M.D.3,
  8. Ralph B. Arlinghaus M.D.3,
  9. Leila Alland M.D.2,‡,
  10. Margaret Dugan M.D.2,§,
  11. Jorge Cortes M.D.1,
  12. Francis Giles M.D.1,
  13. Miloslav Beran M.D.1,¶,*

Article first published online: 2 AUG 2005

DOI: 10.1002/cncr.21299

Issue

Cancer

Cancer

Volume 104, Issue 6, pages 1230–1236, 15 September 2005

Additional Information

How to Cite

Verstovsek, S., Golemovic, M., Kantarjian, H., Manshouri, T., Estrov, Z., Manley, P., Sun, T., Arlinghaus, R. B., Alland, L., Dugan, M., Cortes, J., Giles, F. and Beran, M. (2005), AMN107, a novel aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells. Cancer, 104: 1230–1236. doi: 10.1002/cncr.21299

Author Information

  1. 1

    Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas

  2. 2

    Novartis Institutes for Biomedical Research, Basel, Switzerland

  3. 3

    Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas

  1. †

    Dr. Manley is a full-time employee of Novartis.

  2. ‡

    Dr. Alland is an employee of Novartis and owns stock in the company.

  3. §

    Dr. Dugan is an employee of Novartis.

  4. Fax: (713) 794-4297

*Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Unit 428, P.O. Box 301402, Houston, TX 77230

Publication History

  1. Issue published online: 31 AUG 2005
  2. Article first published online: 2 AUG 2005
  3. Manuscript Accepted: 14 APR 2005
  4. Manuscript Revised: 6 APR 2005
  5. Manuscript Received: 15 DEC 2004

Funded by

  • Novartis

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Keywords:

  • Bcr-Abl kinase inhibitor;
  • AMN107;
  • imatinib;
  • acute lymphoblastic leukemia;
  • in vitro models

Abstract

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.

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