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.
|Source||Clin Cancer Res (2013). Figure 1.GDC-0068|
|Cell Lines||IGROV-1 cell|
|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 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.|
|Incubation time||4 days|
|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|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥90 mg/mL
Ethanol ≥90 mg/mL
Discovery and Preclinical Pharmacology of a Selective ATP-competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors.
Blake et al. J Med Chem. 2012 Aug 30. PMID: 22934575.
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