product name GDC-0084
Description: GDC-0084, also known as RG7666, is a brain penetrant inhibitor of PI3K and mTOR with potential antineoplastic activity. PI3K inhibitor GDC-0084 specifically inhibits PI3K in the PI3K/AKT kinase (or protein kinase B) signaling pathway, thereby inhibiting the activation of the PI3K signaling pathway. This may result in the inhibition of both cell growth and survival in susceptible tumor cell populations. GDC-0084 has excellent human metabolic stability in microsomal and hepatocyte incubations and demonstrated inhibition of pAKT, a key signal within the PI3K pathway, in normal brain tissue.
References: ACS Med Chem Lett. 2016 Feb 16;7(4):351-6; Drug Metab Dispos. 2016 Dec;44(12):1881-1889.
382.42
Formula
C18H22N8O2
CAS No.
1382979-44-3
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 8 mg/mL (20.9 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Synonyms
other peoduct :
| In Vitro |
In vitro activity: GDC-0084 has excellent human metabolic stability in microsomal and hepatocyte incubations and demonstrated inhibition of pAKT, a key signal within the PI3K pathway, in normal brain tissue. GDC-0084 is shown to inhibit the proliferation of several glioma cells in vitro with IC50 ranging from 0.3 to 1.1 μM. GDC-0084 binding to plasma proteins is low, with a free fraction (%) of 29.5±2.7 (n=3) in CD-1 mouse plasma, when tested at 5 μM. Binding to brain tissues from CD-1 mice is higher, with a free fraction of 6.7% (±1; n=3). Kinase Assay: Cell Assay: For transport studies, cells are seeded on 24-well Millicell plates 4 days prior to use(polyethylene terephtalate membrane, 1 μm pore size) at a seeding density of 1.3×105 cells/ml). GDC-0084 is tested at 5 μM in the apical-tobasolateral (A-B) and basolateral-to-apical (B-A) directions. The compound is dissolved in transport buffer consisting of Hanks balanced salt solution with 10 mM HEPES. Lucifer Yellow is used as the paracellular and monolayer integrity marker. GDC-0084 concentrations in the donor and receiving compartments are determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The apparent permeability (Papp), in the apical to A-B and B-A directions, is calculated after 2-hour incubation. |
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| In Vivo | GDC-0084 markedly inhibits the PI3K pathway in mouse brain, causing up to 90% suppression of the pAkt signal. GDC-0084 achieves significant tumor growth inhibition of 70% and 40% against the U87 and GS2 orthotopic models, respectively. GDC-0084 distribution throughout the brain and intracranial tumors leads to potent inhibition of the PI3K pathway. It is being evaluated in patients, and exposures reached at tolerated doses are consistent with those associated with efficacious doses in mouse models. |
| Animal model | Male Sprague−Dawley rats or female CD-1 mice |
| Formulation & Dosage | Formulated in 60% PEG400/10% ethanol(i.v.) or 0.5% methylcellulose with 0.2% Tween 80(p.o.); 1 mg/kg (i.v.);5 or 25 mg/kg (p.o.); i.v. or p.o. |
| References | ACS Med Chem Lett. 2016 Feb 16;7(4):351-6; Drug Metab Dispos. 2016 Dec;44(12):1881-1889. |
