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

Abstract

Background/Aims:Published observations on serum and glucocorticoid regulated kinase 1 (Sgk1) knockout murine models and Sgk1-specific RNA silencing in the RKO human colon carcinoma cell line point to this kinase as a central player in colon carcinogenesis and in resistance to taxanes. Methods:By in vitro kinase activity inhibition assays, cell cycle and viability analysis in human cancer model systems, we describe the biologic effects of a recently identified kinase inhibitor, SI113, characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold, that shows specificity for Sgk1. Results: SI113 was able to inhibit in vitro cell growth in cancer cells derived from tumors with different origins. In RKO cells, this kinase inhibitor blocked insulin-dependent phosphorylation of the Sgk1 substrate Mdm2, the main regulator of 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 SI113 appears 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 with paclitaxel, in colon cancer chemotherapy.

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

“…4, panels A and B). In the SI113 treated samples, expression of BCL2, as well as the phosphorylation of p-MDM2 (serine 166) were reduced, consistently with previously published observations [31,35,44], whereas the expression of p53, BECN1 and LC3BI/II was increased, as expected [31,40]. In the 64 CuCl 2 treated cells we only recorded modifications affecting p53, BCL2 and TCR1.…”

“…The treated cells were prepared for incubation with 1% BSA. The results include counts and percentages of cells in each of the quadrant-defined populations, as well as the mean fluorescence intensity of Annexin V and 7-AAD for each population [39,40]. …”

“…Recently, we found a family of dual SRC/ABL small molecule inhibitors, characterized by a substituted pyrazolo [3,4-d]pyrimidine scaffold, able to inhibit SGK1 and AKT kinase activity [34]. Among these molecules, SI113 has been demonstrated to inhibit SGK1 activity, while being much less effective on AKT1, ABL and SRC [35]. SI113 induces cell death, alters the growth rate, promotes autophagy and synergizes with taxanes and radiotherapy in hepatocarcinoma and glioblastoma cells in vitro as well as in vivo, also by favoring a cellular sensibilization to these treatments [35][36][37][38].…”

“…Among these molecules, SI113 has been demonstrated to inhibit SGK1 activity, while being much less effective on AKT1, ABL and SRC [35]. SI113 induces cell death, alters the growth rate, promotes autophagy and synergizes with taxanes and radiotherapy in hepatocarcinoma and glioblastoma cells in vitro as well as in vivo, also by favoring a cellular sensibilization to these treatments [35][36][37][38]. Based on the apparent lack of toxicity and the consistent ability of SI113 to negatively modulate the chemo-radio resistance [36], in the present work we investigated the potential combined use of 64 CuCl 2 and SI113 in GBMs cellular models.…”

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

“…Until now, several SGK1 inhibitors have been developed, including GSK650394, LY294002, SI113, and EMD638683 (Towhid et al 2013, D'Antona et al 2015. Compared with others, EMD638683 is the most selective SGK1 inhibitor (Towhid et al 2013).…”