Bosutinib -: Dual Src and Abl kinase inhibitor treatment of solid tumors treatment of CML and Ph+ ALL

Bosutinib (SKI-606) is a potent inhibitor of Src kinase activity, having IC50 values of 1-3 nM in isolated Src enzyme assays. Bosutinib inhibits Src autophosphorylation and the phosphorylation of several known Src substrate proteins in multiple human cancer lines. Bosutinib is orally effective in nude mouse xenograft models, including HT-29, COLO 205, HCT 116 and DLD-1 colorectal tumors and MDA-MB-231 breast tumors, as well as in several in vivo models of metastasis. Like many other Src inhibitors, bosutinib is also a potent inhibitor of Abl kinase activity, having an IC50 of 1 nM in an enzyme assay. It is a potent antiproliferative agent in chronic myelogenous leukemia (CML) cell lines and inhibits the phosphorylation of Abl substrate proteins in these cells. A 5-day oral regimen of bosutinib caused tumor regression and some cures in a CML xenograft model. Bosutinib was also orally active in models of imatinib-resistant CML. Bosutinib is currently in clinical trials for the treatment of both solid tumors and CML.