Novel dual Src/Abl inhibitors for hematologic and solid malignancies.

A review. C-Src and Bcr-Abl are 2 non-receptor or cytoplasmic tyrosine kinases (TKs) that play important roles in the development of solid and hematol. malignancies. Indeed, Src is overexpressed or hyperactivated in a variety of solid tumors, while Bcr-Abl is the causative agent of chronic myeloid leukemia (CML), where Src is also involved. The 2 enzymes share significant sequence homol. and remarkable structural resemblance. ATP-competitive compds. originally developed as Src inhibitors, showed to be also potent Abl inhibitors. Dasatinib, the first dual Src/Abl inhibitor approved by the US FDA in 2006 for the treatment of imatinib-resistant CML, is currently being tested in several clin. trials for the treatment of different solid tumors. SKI-606 and AZD0530 are 2 other important dual Src/Abl inhibitors extensively tested in animal models and in clin. trials, but not entered into therapy yet. In this review we will report the latest results regarding dasatinib, SKI-606 and AZD0530, but also the knowledge on new compds. that have appeared in the literature in the last few years, including AP24163, AP24534, XL228, DC2036. We will focus on the most recent clin. trials or on preclin. studies that are in progress on these small-mol. TK inhibitors that represent a targeted therapy with high potential against cancer. Molecularly targeted therapies, including the inhibition of specific TKs hyperactivated or overexpressed in many human cancers, could be less toxic than the classical non-specific cytotoxic chemotherapeutic agents; they could offer important therapeutic effects, esp. if used in assocn. with other agents such as monoclonal antibodies.