Influence on the phosphorylation of AKT or GSK3, but inhibited the phosphorylation of p70S6K and S6 ribosomal protein and less than 2 hours, PD0325901 PD325901 st More strongly, by 8 clock, a T ACTION consistent with the inhibition of mTORC1. In accordance with its relatively small influence on mTOR kinase activity t, IC50 of 8 hours of the four synthetic inhibitors of the ribosomal S6 protein phosphorylation of Ser235 is substantially less than that of rapamycin. because the phosphatidylinositol 3-kinase inhibitors, particularly at GDC 0941, shows st rkere antiproliferative activity of t against IGROV ovarian cancer cells compared to U87MG glioblastoma cells, we examined the effects of IP on 103 and GDC 0941 Ser473 phosphorylation of AKT as sensitive biomarker for the phosphatidylinositol 3-kinase inhibition in IGROV 1 cells and compared the results with the above described for U87MG cells.
IC50 values for inhibition of phosphorylation of Ser473 of AKT in IGROV 1 cells after 2 or 8 hours of exposure of 18 2 and 17 4 nmol / l and IP 103 and 18-1 and 38 13 nmol / l, respectively for GDC 0941st These values of the line ovarian carcinoma were remarkable Similar values in U87MG glioblastoma cells, despite lower antiproliferative potency inhibitors of glioblastoma line. Close Of course, we compared the IC 50 values for the inhibition of phosphorylation of AKT Ser473 in three lines of human cancer cells of the colon. Although antiproliferative GI50-PI values were 103 37-times of 22 nmol / l to 827 nmol / L, the IC50 values for inhibition of phosphorylation of AKT at Ser473 after 2 hours of exposure, only 2 times of 18 nmol / l to 38 nmol / L for varied.
In the case of GDC 0941, the antiproliferative GI50 values were 9-180 times nmol / l to 1627 nmol / l, may need during the IC50 values for inhibition of phosphorylation at Ser473 Akt After 2 hours after treatment only 2 times of 14 nmol / L to 33 nmol / l varies, if these results for cancer c lines Lon associated with ovarian cancer and glioblastoma cell data into account, it is clear that the Ausma Inhibition of phosphatidylinositol 3-kinase remarkable similar in all cancer cell lines, w while the consequences are in the form of m resembled antiproliferative very different, suggesting a different anti-proliferative response to a given degree of blockade of phosphatidylinositol 3-kinase.
The intravenous pharmacokinetics of PI 540 and PI 620 The pharmacokinetics of PI 540 and PI 620 S in Mice and PO are at 10 mg / kg showed. 2A and B, respectively. Both compounds showed a high plasma clearance with a very big s volumes of distribution. The huge distributionwas best by high concentrations in the tissue CONFIRMS, as shown in rats at plasma-money ratios of 31 and 13.9, respectively after intravenous Water administration. Terminal half-lives after iv administration were short in the plasma, but in most tissues. Both compounds were orally bioavailable poorly absorbed, with values of 10%, but they were also from the Bauchh cave and showed linear pharmacokinetics at doses well tolerated. This led to tumor concentrations above GI50 in athymic M Nozzles which xenografts of U87MG glioblastoma cells for 4 hours at 100 mg / kg IP 540 and 50 mg / kg IP 620th Based on the planes with tumors, the concentrations