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GDC-0068 (RG7440) is a novel, ATP-competitive and orally bioavailable Akt inhibitor with IC50 values of 5 nM, 18 nM and 8 nM for Akt1, Akt2 and Akt3, respectively. Ipatasertib (GDC-0068) demonstrates potent inhibition of all three Akt isoforms in biochemical assays, but poor inhibition of other AGC family kinases. Moreover, GDC-0068 selectively inhibits cell cycle progression and viability of cancer cell lines driven by PI3K/Akt signaling pathway, including those with defects in the tumor suppressor PTEN, oncogenic mutations in PIK3CA, and amplification of HER2. GDC-0068 (Ipatasertib) blocks the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. GDC-0068 (RG7440) shows good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust anti-tumor response in xenograft models in which the PI3K-Akt-mTOR pathway is activated.
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Source | Clin Cancer Res (2013). Figure 1.GDC-0068 |
| Method | Western blot | |
| Cell Lines | IGROV-1 cell | |
| Concentrations | 200 nmol/L | |
| Incubation Time | 4 h | |
| Results | GDC-0068 showed more than 600 and more than 100-fold selectivity for Akt1 in IC50 against the closely related kinases PKA and p70S6K, respectively |
| Cell Experiment | |
|---|---|
| Cell lines | MCF10A cells with or without PTEN knockout (KO) |
| Preparation method | Cell viability assays The 384-well plates were seeded with 2,000 cells per well in a volume of 54 μL per well followed by incubation at 37°C under 5% CO2 overnight (∼16 hours). Compounds were diluted in dimethyl sulfoxide (DMSO) to generate the desired stock concentrations then added in a volume of 6 μL per well. All treatments were tested in quadruplicates. After 4 days incubation, relative numbers of viable cells were estimated using CellTiter-Glo (Promega) and total luminescence was measured on a Wallac Multilabel Reader (PerkinElmer). The concentration of drug resulting in IC50 was calculated from a 4-parameter curve analysis (XLfit, IDBS software) and was determined from a minimum of 3 experiments. For cell lines that failed to achieve an IC50, the highest concentration tested (10 μmol/L) is listed. |
| Concentrations | 0~10µM |
| Incubation time | 4 days |
| Animal Experiment | |
|---|---|
| Animal models | MCF7-neo/HER2 tumor xenograft model |
| Formulation | 0.5% methylcellulose/0.2% Tween-80 (MCT) |
| Dosages | 0,12.5, 25, 50, 75, 100mg/kg |
| Administration | oral gavage |
| Molecular Weight | 458 |
| Formula | C24H32ClN5O2 |
| CAS Number | 1001264-89-6 |
| Solubility (25°C) | DMSO 90 mg/mL Ethanol 60 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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| FPA-124
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