GDC-0084 |
Catalog No.GC10228
One-Click Copy Product Info
|
PI3K and mTOR inhibitor, brain-permeable
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1382979-44-3
Sample solution is provided at 25 µL, 10mM.
_1-3.$$$39978408@51.jpg');)
_1-9.$$$38538795@65.jpg');)
_1-9.$$$39112701@51.jpg');)
_1-7.$$$37316672@70.jpg');)
_366-372.$$$36198801@70.jpg');)
.$$$38565142@65.jpg');)
_1867-1883.$$$33248023@67.jpg');)
_eads6055.$$$39977546@45.jpg');)
_eadm9805.$$$40080571@45.jpg');)
_eadj3020.$$$39666821@45.jpg');)
_1-20.$$$39757301@28.jpg');)
_1-24.$$$38898113@28.jpg');)
_273-287.$$$36806353@46.jpg');)
_1-16.$$$37156877@44.jpg');)
_1-19.$$$37460805@44.jpg');)
_1291-1307.$$$34518654@46.jpg');)
GDC-0084 is a potent and brain penetrant inhibitor of PI3K and mTOR with Ki values of 2 nM and 70 nM for PI3Kα and mTOR, respectively [1].
Glioblastoma (GBM) is the most common primary brain tumor in adults and aberrant PI3K signaling is associated with more than 80% of cases. The PI3K pathway represents a potential target for the treatment of this disease and the inhibitors would need to freely cross the blood-brain barrier (BBB) [1][2].
GDC-0084 is a potent and brain penetrant inhibitor of PI3K and mTOR. In vitro kinase assay, GDC-0084 exhibited Ki values of 2 nM, 46 nM, 3 nM, 10 nM and 70 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ and mTOR, respectively. In five different GBM cell lines, GDC-0084 had antiproliferative activities with EC50 values ranging from 0.3 to 1.1 μM. GDC-0084 has excellent human metabolic stability in microsomal and hepatocyte incubations [1]. In transfected cell lines over-expressing human or mouse P-gp or BCRP, GDC-0084 was a poor substrate of these efflux transporters. In mice brain, GDC-0084 significantly lowered pAkt and pS6 levels [2].
In rats after a 15 mg/kg dose of GDC-0084, the total brain-to-plasma ratio was 1.9-3.3. In subcutaneous U87 glioblastoma tumor xenograft mice model, GDC-0084 significantly inhibited tumor growth in a dose-dependent way. GDC-0084 also concentration-dependently inhibited pAKT [1].
References:
[1]. Heffron TP1, Ndubaku CO1, Salphati L1, et al. Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR. ACS Med Chem Lett. 2016 Feb 16;7(4):351-6.
[2]. Salphati L, Alicke B, Heffron TP, et al. Brain Distribution and Efficacy of the Brain Penetrant PI3K Inhibitor GDC-0084 in Orthotopic Mouse Models of Human Glioblastoma. Drug Metab Dispos. 2016 Dec;44(12):1881-1889. Epub 2016 Sep 16.
Kinase experiment: | Enzymatic activity of PI3Kα is measured using a fluorescence polarization assay that monitors formation of the product 3,4,5-inositoltriphosphate molecule (PIP3) as it competes with fluorescently labeled PIP3 for binding to the GRP-1 pleckstrin homology domain protein. An increase in phosphatidyl inositide-3-phosphate product results in a decrease in fluorescence polarization signal as the labeled fluorophore is displaced from the GRP-1 protein binding site. PI3Kα is expressed and purified as heterodimeric recombinant protein. PI3Kα is assayed under initial rate conditions in the presence of 10 mM Tris (pH 7.5), 25 uM ATP, 9.75 uM PIP2, 5% glycerol, 4 mM MgCl2, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM dithiothreitol, 2% (v/v) DMSO at a 60 ng/mL concentration of PI3Kα. After assay for 30 min at 25°C, reactions are terminated with a final concentration of 9 mM EDTA, 4.5 nM TAMRA-PIP3, and 4.2 ug/mL GRP-1 detector protein before reading fluorescence polarization on an Envision plate reader. IC50s are calculated from the fit of the dose-response curves to a 4-parameter equation. Apparent Kis, where measured, are determined at a fixed concentration of ATP near the measured Km for ATP for PI3Kα, and are calculated by fitting of the dose-response curves to an equation for tightbinding competitive inhibition[1]. |
Animal experiment: | Mice[1] PTEN-null U-87 MG/M human glioblastoma cancer cells are cultured in RPMI 1640 media plus 1% L-glutamine with 10% fetal bovine serum. Cells in log-phase growth are harvested and resuspended in HBSS:Matrigel (1:1, v:v) for injection into female NCr nude mice aged 20 weeks. Animals receive five million cells subcutaneously in the right lateral thorax in 0.1 mL. Mice bearing established tumors in the range of 200-500 mm3 are separated into groups of equally sized tumors (n=6-7/group) to receive escalating doses of GDC-0084 (Compound 16). GDC-0084 is formulated once weekly in 0.5% methylcellulose and 0.2% Tween-80 at concentrations needed for target doses in a volume of 0.2 mL. All formulations are stored in a refrigerator and brought to room temperature and mixed well by vortex before oral administration by gavage once daily for 23 days. Tumor volumes are calculated. Changes in body weights are reported as a percentage change from the starting weight. |
References: [1]. Heffron TP, et al. Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR. ACS Med Chem Lett. 2016 Feb 16;7(4):351-6. | |
| Cas No. | 1382979-44-3 | SDF | |
| Chemical Name | 5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl)pyrimidin-2-amine | ||
| Canonical SMILES | NC1=NC=C(C2=NC(N3CCOCC3)=C4N=C5C(C)(C)OCCN5C4=N2)C=N1 | ||
| Formula | C18H22N8O2 | M.Wt | 382.42 |
| Solubility | Soluble in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 2.6149 mL | 13.0746 mL | 26.1493 mL |
| 5 mM | 523 μL | 2.6149 mL | 5.2299 mL |
| 10 mM | 261.5 μL | 1.3075 mL | 2.6149 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)
Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL saline, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >98.00% Appearance: A solid
- COA (Certificate of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 9 reference(s) in Google Scholar.)