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GSK690693 is a small molecule ATP-competitive inhibitor of the pro-survival kinase Akt. Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3, the pro-apoptotic protein Bad, as well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). Intraperitoneal administration of GSK690693 in uncompromised mice resulted in the inhibition of GSK3b and repeated dosing of 25 in BT474 breast carcinoma xenograft mice produced a significant delay in tumor growth. GSK690693 inhibited cell growth in vitro with IC(50) values between 6.5 nM and >10µM. In vivo, GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts, most notably in all 6 osteosarcoma models, but not in any of the 8 ALL xenografts tested. No objective responses were observed and only one solid tumor met EFS T/C criteria for intermediate activity.
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Source | Clin Cancer Res (2010). Figure 3. GSK690693 |
| Method | Cell Viability Assay | |
| Cell Lines | T cells | |
| Concentrations | 0, 10 or 20 μM | |
| Incubation Time | 72 hrs | |
| Results | Thymic lymphoma cells from Lck-MyrAkt2 mice responded rapidly to treatment with GSK690693, with a 2–3 fold increase in apoptotic cells observed within 24 hrs |
| Cell Experiment | |
|---|---|
| Cell lines | 786-O, H157, MDA-MB-468, and PC-3, LNCaP and BT474 cells |
| Preparation method | Proliferation assay. Cell proliferation assays were performed for a number of cell lines as described earlier with some modifications. For these assays, cells were plated at densities that allowed untreated cells to grow logarithmically during the course of a 3-d assay. Briefly, cells were plated in 96- or 384-well plates in culture medium containing 10% fetal bovine serum and incubated overnight at 37° C in 5% CO2. Cells were then treated with GSK690693 (ranging from 30 μmol/L-1.5 nmol/L) and incubated for 72 h. Cell proliferation was measured using the CellTiter Glo (Promega) reagent according to the manufacturer's protocol. Data were analyzed using the XLFit (IDBS Ltd.) curve-fitting tool for Microsoft Excel. IC50 values were obtained by fitting data to Eq. 2. |
| Concentrations | 1.5nM~30 μ M |
| Incubation time | 3 days |
| Animal Experiment | |
|---|---|
| Animal models | Mice bearing established human tumor xenografts (BT-474, HCC-1954, Lncap, SKOV3) |
| Formulation | formulated in either 4% DMSO/40% hydroxypropyl-β-cyclodextrin in water (pH 6.0) or 5% dextrose (pH 4.0) |
| Dosages | once daily at 10, 20, and 30 mg/kg for 21 days |
| Administration | i.p. |
| Molecular Weight | 425.48 |
| Formula | C21H27N7O3 |
| CAS Number | 937174-76-0 |
| Solubility (25°C) | DMSO 26 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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| MK-2206 2HCl
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