Apitolisib (GDC-0980; GNE 390; RG 7422) is a potent, highly selective, oral, dual inhibitor of class I PI3K and mTOR. Apitolisib (GDC-0980) demonstrates broad preclinical activity in breast, ovarian, lung, and prostate cancer models. Apitolisib (GDC-0980) can potently inhibit for isoforms of p110 including p110-alpha, p110-beta, p110-gamma and p110-delta. The IC50 value for inhibition of p110-alpha, p110-beta, p110-gamma and p110-delta by GDC-0980 is 5 nM,27 nM,7 nM and 14 nM. Besides the inhibition of Phosphoinositide 3-kinase, GDC-0980 also show strong inhibition to mTOR, which is a downstream target of akt but not only in PI3K signaling pathway. The Ki value for mTOR is 17 nM.
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Source | Biochem Biophys Res Commun (2014). Figure 3. GDC-0980 |
| Method | Western blotting | |
| Cell Lines | PANC-1 cells and Capan-1 cells | |
| Concentrations | 1 μM | |
| Incubation Time | 24 h | |
| Results | Western blotting results in Fig. 1B showed clearly that GDC-0980 (1 μM) dramatically inhibited phosphorylation of AKT (Ser-473 and Thr-308) and S6K1 (Thr-389) in both PANC-1 cells and Capan-1 cells. |
| Cell Experiment | |
|---|---|
| Cell lines | NSCLS cell lines, colon cancer cell lines and etc. |
| Preparation method | Cell viability assays Three hundred and eighty-four–well plates were seeded with 2,000 cells/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 to generate the desired stock concentrations then added in a volume of 6 μL per well. All treatments were tested in quadruplicate. 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 50% inhibition of cell viability (IC50) or 50% maximal effective concentration (EC50) was determined using Prism software (GraphPad). For cell lines that failed to achieve an IC50 the highest concentration tested (20 μmol/L) is listed. |
| Concentrations | 0~5µM |
| Incubation time | 4 days |
| Animal Experiment | |
|---|---|
| Animal models | MCF7-neo/HER2 tumor-bearing mice |
| Formulation | 0.5% methylcellulose with 0.2% Tween-80 |
| Dosages | 7.5 mg/kg |
| Administration | oral gavage |
| Molecular Weight | 498.6 |
| Formula | C23H30N8O3S |
| CAS Number | 1032754-93-0 |
| Solubility (25°C) | DMSO 15 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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