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Dual tyrosine kinase inhibitors in chronic myeloid leukemia

Leukemia volume 19, pages 1872–1879 (2005)Cite this article

Abstract

The Bcr-Abl inhibitor imatinib mesylate induces complete hematologic and cytogenetic remissions in most newly diagnosed chronic myeloid leukemia (CML) patients, but relatively few of them achieve molecular remission. In addition, imatinib is much less effective in advanced phase-CML as well as in Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL), mainly due to the development of drug resistance. The challenge for the future is to improve current clinical results with kinase inhibitors in CML, developing strategies that can eradicate residual disease and overcome or prevent resistance. ‘Dual’ Src and Abl kinase inhibitors are an attractive class of compounds, since (a) these molecules are able to bind Bcr-Abl with less stringent conformational requirements with respect to imatinib, therefore allowing for efficient inhibition of several, resistance-associated mutant forms of Bcr-Abl; (b) Src kinases have been shown to be involved in Bcr-Abl-mediated leukemogenesis as well as upregulated in some patients resistant to imatinib. Here, we review the development, the mode of action and the preclinical or early clinical evaluation of several novel dual Src and Abl kinase inhibitors.

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Acknowledgements

We thank Sabrina Colarossi, Tiziana Grafone, Marilina Amabile, Angela Poerio, Ilaria Iacobucci, Fabrizio Pane and Giuseppe Saglio for helpful discussion about this review data. This study was supported by European Leukemia Net, Cofin 2003 (M Baccarani), AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2001 and Ateneo 60% grants.

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  1. Institute of Hematology and Medical Oncology ‘Seràgnoli’, University of Bologna, Bologna, Italy

    G Martinelli, S Soverini, G Rosti & M Baccarani

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Correspondence to G Martinelli.

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Martinelli, G., Soverini, S., Rosti, G. et al. Dual tyrosine kinase inhibitors in chronic myeloid leukemia. Leukemia 19, 1872–1879 (2005). https://doi.org/10.1038/sj.leu.2403950

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