GDC-0084 (Paxalisib; RG7666)

Alias: Paxalisib; RG 7666; RG7666; RG-7666; GDC0084; GDC-0084; GDC 0084
Cat No.:V2541 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.
GDC-0084 (Paxalisib; RG7666) Chemical Structure CAS No.: 1382979-44-3
Product category: PI3K
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

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.

Biological Activity I Assay Protocols (From Reference)
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

[1]. ACS Med Chem Lett . 2016 Feb 16;7(4):351-6.

[2]. Drug Metab Dispos . 2016 Dec;44(12):1881-1889.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
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 Data
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.

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Clinical Trial Information
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
Biological Data
  • GDC-0084

    GDC-0084

    Inhibition of p-AKT by16in normal mouse brain tissue along with corresponding brain and unbound brain concentrations.2016 Feb 16;7(4):351-6.




  • GDC-0084

    In vivo efficacy of16versus U87 MG/M human glioblastoma xenografts.2016 Feb 16;7(4):351-6.

  • GDC-0084

    Effect of 16 on the PD marker pAKT in the U87 MG/M human glioblastoma xenograft model after 24 days of continuous dosing.


    GDC-0084Synthetic Route to Obtain Tricyclic Purine-Based Brain Penetrant PI3K Inhibitor16.2016 Feb 16;7(4):351-6.

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