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GDC-0084

Cat. No. M6304
GDC-0084 Structure
Size Price Availability Quantity
5mg USD 130 In stock
10mg USD 200 In stock
50mg USD 680 In stock
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Quality Control
  • Current batch:
  • Purity >98%
  • COA
  • MSDS
Biological Activity

In vitro: 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).

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.

Protocol
Cell Experiment
Cell lines Darby canine kidney (MDCK) cells (MDR1-MDCKI cells)
Preparation method 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.
Concentrations 5 μM
Incubation time 2 h
Animal Experiment
Animal models Male Sprague−Dawley rats or female CD-1 mice
Formulation 60% PEG400/10% ethanol(i.v.) or 0.5% methylcellulose with 0.2% Tween 80(p.o.)
Dosages 1 mg/kg(i.v.);5 or 25 mg/kg(p.o.)
Administration i.v. or p.o.
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
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 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.

Chemical Information
Molecular Weight 382.42
Formula C18H22N8O2
CAS Number 1382979-44-3
Purity >98%
Solubility 8 mg/mL in DMSO
Storage at -20°C
References

Brain Distribution and Efficacy of the Brain Penetrant PI3K Inhibitor GDC-0084 in Orthotopic Mouse Models of Human Glioblastoma.
Salphati L, et al. Drug Metab Dispos. 2016 Dec;44(12):1881-1889. PMID: 27638506.

Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR.
Heffron TP, et al. ACS Med Chem Lett. 2016 Feb 16;7(4):351-6. PMID: 27096040.

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  Catalog
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Keywords: GDC-0084 supplier, PI3K, inhibitors

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