Size | Price | Stock | Qty |
---|---|---|---|
5mg |
|
||
10mg |
|
||
25mg |
|
||
50mg |
|
||
100mg |
|
||
250mg |
|
||
500mg |
|
||
Other Sizes |
|
Purity: ≥98%
GDC-0084 (Paxalisib; RG7666) is a novel, potent and brain penetrant inhibitor of phosphatidylinositol 3-kinase (PI3K) and mTOR with potential antineoplastic activity. It has Ki values of 2 nM, 46 nM, 3 nM, 10 nM and 70 nM for PI3Kα PI3Kβ, PI3Kδ, PI3Kγ and mTOR, respectively.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. In susceptible populations of tumor cells, this may prevent both cell growth and survival. GDC-0084 inhibits pAKT, a crucial signal in the PI3K pathway, in healthy brain tissue and exhibits excellent human metabolic stability in microsomal and hepatocyte incubations.
Targets |
PI3Kα (Ki = 2 nM); PI3Kδ (Ki = 3 nM); PI3Kγ (Ki = 10 nM); PI3Kβ (Ki = 46 nM); mTOR (Ki = 70 nM)
|
---|---|
ln 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[1]. With an IC50 ranging from 0.3 to 1.1 μM, GDC-0084 has been shown to suppress the growth of several glioma cells in vitro. With a free fraction (%) in CD-1 mouse plasma of 29.5±2.7 (n=3) when tested at 5 M, GDC-0084 binding to plasma proteins is weak. A higher free fraction of 6.7% (±1; n=3)[2] indicates stronger binding to the brain tissues of CD-1 mice.
|
ln Vivo |
GDC-0084 markedly inhibits the PI3K pathway in mouse brain, causing up to 90% suppression of the pAkt signal. GDC-0084 effectively inhibits tumor growth in the U87 and GS2 orthotopic models by 70% and 40%, respectively. The PI3K pathway is effectively inhibited by the distribution of GDC-0084 in intracranial tumors and the brain. It is being tested on humans, and the exposures at doses that are safe are similar to those linked to effective doses in mouse models[2].
|
Enzyme Assay |
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.
|
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). Tests are conducted on GDC-0084 at 5 μM in both the apical-to-basolateral (A-B) and basolateral-to-apical (B-A) directions. In a transport buffer made up of 10 mM HEPES in Hanks' balanced salt solution, the substance is dissolved. As a marker for the integrity of monolayers and paracytic layers, Lucifer Yellow is employed. Utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, the concentrations of GDC-0084 in the donor and receiving compartments were found. After a 2-hour incubation, the apparent permeability (Papp) in the apical to A-B and B-A directions is calculated.
|
Animal Protocol |
Male Sprague−Dawley rats or female CD-1 mice
1 mg/kg(i.v.);5 or 25 mg/kg(p.o.) i.v. or p.o. |
References |
Molecular Formula |
C18H22N8O2
|
---|---|
Molecular Weight |
382.4197
|
Exact Mass |
382.1866
|
Elemental Analysis |
C, 56.53; H, 5.80; N, 29.30; O, 8.37
|
CAS # |
1382979-44-3
|
Appearance |
Solid powder
|
SMILES |
CC1(C2=NC3=C(N2CCO1)N=C(N=C3N4CCOCC4)C5=CN=C(N=C5)N)C
|
InChi Key |
LGWACEZVCMBSKW-UHFFFAOYSA-N
|
InChi Code |
InChI=1S/C18H22N8O2/c1-18(2)16-22-12-14(25-3-6-27-7-4-25)23-13(11-9-20-17(19)21-10-11)24-15(12)26(16)5-8-28-18/h9-10H,3-8H2,1-2H3,(H2,19,20,21)
|
Chemical Name |
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl)pyrimidin-2-amine
|
Synonyms |
Paxalisib; RG 7666; RG7666; RG-7666; GDC0084; GDC-0084; GDC 0084
|
HS Tariff Code |
2934.99.9001
|
Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
Solubility (In Vitro) |
DMSO: ~8 mg/mL (~20.9 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
---|
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.6149 mL | 13.0746 mL | 26.1493 mL | |
5 mM | 0.5230 mL | 2.6149 mL | 5.2299 mL | |
10 mM | 0.2615 mL | 1.3075 mL | 2.6149 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT03522298 | Active Recruiting |
Drug: Paxalisib (GDC-0084) |
Glioblastoma, Adult | Kazia Therapeutics Limited | May 15, 2018 | Phase 2 |
NCT03696355 | Completed | Drug: GDC-0084 Radiation: radiation therapy |
Brain and Central Nervous System Tumors |
St. Jude Children's Research Hospital |
November 19, 2018 | Phase 1 |
NCT03765983 | Recruiting | Drug: GDC-0084 Drug: Trastuzumab |
Breast Cancer | Dana-Farber Cancer Institute | February 11, 2019 | Phase 2 |
NCT03970447 | Recruiting | NCT03970447 Drug: VAL-083 |
Glioblastoma | Global Coalition for Adaptive Research |
July 30, 2019 | Phase 2 Phase 3 |
Inhibition of p-AKT by16in normal mouse brain tissue along with corresponding brain and unbound brain concentrations.ACS Med Chem Lett.2016 Feb 16;7(4):351-6. |
In vivo efficacy of16versus U87 MG/M human glioblastoma xenografts.ACS Med Chem Lett.2016 Feb 16;7(4):351-6. td> |
Effect of 16 on the PD marker pAKT in the U87 MG/M human glioblastoma xenograft model after 24 days of continuous dosing. Synthetic Route to Obtain Tricyclic Purine-Based Brain Penetrant PI3K Inhibitor16.ACS Med Chem Lett.2016 Feb 16;7(4):351-6. td> |