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.
Cell Experiment | |
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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 | |
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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 |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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