¹Institute of Hematology and Medical Oncology 'Seràgnoli', University of Bologna, Bologna, Italy

Correspondence: Professor G Martinelli, Institute of Hematology and Medical Oncology 'Seràgnoli', University of Bologna, Via Massarenti 9 – 40138 Bologna, Italy. Fax: +39 051 6364037; E-mail: gmartino@kaiser.alma.unibo.it

Received 23 March 2005; Accepted 12 August 2005; Published online 22 September 2005.

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.