SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

Background/Aims: Published observations on serum and glucocorticoid regulated kinase1 (Sgk1) knockout murine models and Sgk1-specific RNA silencing in the RKO human coloncarcinoma cell line point to this kinase as a central player in colon carcinogenesis and inresistance to taxanes. Methods: By in vitro kinase activity inhibition assays, cell cycle andviability analysis in human cancer model systems, we describe the biologic effects of a recentlyidentified kinase inhibitor, SI113, characterized by a substituted pyrazolo[3,4-d]pyrimidinescaffold, that shows specificity for Sgk1. Results: SI113 was able to inhibit in vitro cell growthin cancer cells derived from tumors with different origins. In RKO cells, this kinase inhibitorblocked insulin-dependent phosphorylation of the Sgk1 substrate Mdm2, the main regulatorof p53 protein stability, and induced necrosis and apoptosis when used as a single agent.Finally, SI113 potentiated the effects of paclitaxel on cell viability. Conclusion: Since SI113appears to be effective in inducing cell death in RKO cells, potentiating paclitaxel sensitivity,we believe that this new molecule could be efficiently employed, alone or in combination withpaclitaxel, in colon cancer chemotherapy.