c-Src is a proto-oncogene involved in the genesis of and invasion by many
cancers. This non-
receptor tyrosine kinase also plays a crucial role in bone homeostasis, since inhibition or deletion of c-Src impairs the function of osteoclasts, the bone resorbing cells. It is thus conceivable that c-Src could be a suitable target for the pharmacological treatment of
cancers, skeletal
metastases and diseases of bone loss, such as
osteoporosis. The pyrrolo-
pyrimidines CGP77675 and
CGP76030 proved to be effective in preventing bone loss in animal models, while the effect of
AZD0530, a dually active inhibitor of c-Src and Bcr-ABL, on
bone resorption, has been tested in a Phase I clinical trials with promising results. As far as the metastatic
bone disease is concerned, c-Src inhibitors could potentially have inhibitory effects both on osteoclasts and on tumour cells, and could disrupt the vicious circle established between these cell types in the bone microenvironment. In accord with this idea,
CGP76030 is able to reduce the incidence of osteolytic lesions and of visceral
metastases, and to suppress morbidity and lethality in a bone
metastasis mouse model without obvious adverse effects. The
purine-based c-Src inhibitor
AP23451 and the dual c-Src/Abl inhibitors
AP22408 and
AP23236 proved efficacious in reducing bone
metastases in preclinical studies. These results open a new avenue for the development of
innovative therapies for the treatment of bone metastatic disease.