Dual Inhibitors of Src and Abl Tyrosine Kinases

Chronic myelogenous leukemia (CML) is characterized by the expression of Bcr-Abl, a constitutively active form of the Abl tyrosine kinase. Gleevec, a small molecule Abl inhibitor developed by Novartis, is effective in treating early-stage CML patients, however those with advanced disease often acquire resistance to the drug. In many cases, this resistance is associated with mutations in the Abl kinase domain that no longer allow Gleevec to bind to the protein. In contrast to Gleevec, which does not inhibit members of the Src family of kinases (SFKs), several compounds initially identified as Src inhibitors also inhibit Abl. Crystallography showed that while Gleevec binds only to the inactive conformation of the Abl catalytic domain, PD 173955, a dual Src / Abl inhibitor, binds to both the active and inactive conformations. This finding is consistent with the activity of several Src / Abl inhibitors against cell lines harboring certain Gleevec resistant mutated forms of Bcr-Abl. In addition, since SFKs are implicated in Bcr-Abl signaling, these dual Src / Abl inhibitors may prove to be highly effective agents for the treatment of CML, both as first line agents and for those patients who develop Gleevec resistance. This review summarizes the considerable efforts focused on the design of dual inhibitors of Src and Abl kinases.