Src is one of the oldest and most studied proto-oncogenes. A constitutively active form of this non-receptor tyrosine kinase, v-Src kinase, encoded by the mutant Src gene within the Rous Sarcoma Virus genome can transform fibroblasts. Although evidence for activating mutations within the cellular Src homologue, c-Src, in human tumours is limited and controversial, there is a significant body of data describing high levels of c-Src kinase expression and activity in many human tumour types. In many cases, this appears to be driven by post-translational activation mechanisms. This has been linked to poor clinical prognosis, tumour progression and in particular, tumour dissemination. These observations are supported by accumulating pre-clinical data suggesting that increased Src kinase activity predominantly leads to changes in cell behaviour that contribute to an invasive tumour phenotype. The increased understanding of the role of Src kinase in multiple signalling pathways together with structural knowledge of the kinase and their implications for rational drug design has led to renewed interest in Src as a therapeutic target in cancer. Here we report on the structure activity relationships and key pre-clinical findings that led to the discovery of AZD0530 as an orally available, highly potent, dual specific inhibitor of Src and Abl kinases. Clinical studies in healthy volunteers have demonstrated the tolerability of AZD0530 during once daily continuous oral dosing and have provided, for the first time, pharmacodynamic data to indicate an AZD0530 dose dependent inhibition of Src dependant activity in man. Clinical plans to explore the Src and Abl kinase activity of this well tolerated and clinically active compound are currently being developed.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]