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Purity: =99.9%
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)
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|---|---|
| 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.
- Antiproliferative activity：GDC-0084 exhibits antiproliferative activity in five glioblastoma (GBM) cell lines, with EC₅₀ values ranging from 0.3 to 1.1 μM. [1] - Signaling pathway inhibition：It can inhibit pAKT, a key signaling molecule in the PI3K pathway, in normal brain tissues. [1] - Metabolic stability：Demonstrates excellent human metabolic stability in microsomal and hepatocyte incubation experiments. [2] - Efflux transporter substrate property：GDC-0084 is a poor substrate for efflux transporters in transfected cell lines overexpressing human or mouse P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). [2] |
| 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].
- PI3K pathway inhibition：In mouse brains, GDC-0084 significantly inhibits the PI3K pathway, leading to up to 90% suppression of pAKT signaling. [1] - Tumor growth inhibition：It achieves 70% and 40% tumor growth inhibition rates in U87 and GS2 orthotopic models, respectively. [1] - Brain distribution：Matrix-assisted laser desorption ionization (MALDI) imaging shows that GDC-0084 is uniformly distributed in the brain and intracranial U87 and GS2 tumors. [1] |
| 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.
inase activity assay：GDC-0084 is incubated with PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, and mTOR kinases respectively. The inhibitory effects on each kinase are determined through specific kinase activity detection methods, resulting in Ki values of 2 nM, 46 nM, 3 nM, 10 nM, and 70 nM, respectively. [1] |
| 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.
- Cell proliferation assay：Different concentrations of GDC-0084 (0 - 10 μM) are added to five GBM cell lines. After culturing for a certain period (e.g., 72 hours), cell viability is detected by methods such as MTT or CCK-8, and the EC₅₀ values are calculated to range from 0.3 to 1.1 μM. [1] - Efflux transporter-related assay：Transfected cell lines overexpressing P-gp or BCRP are cultured separately. GDC-0084 is added, and after culturing for a period of time, the intracellular drug concentration is detected and compared with cells not overexpressing the transporters to determine whether it is a substrate of the efflux transporters. [2] |
| 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. - Intracranial tumor model experiment：U87 or GS2 cells are inoculated into the intracranial cavity of mice to construct orthotopic tumor models. When the tumors grow to a certain extent, the mice are randomly divided into groups and administered GDC-0084 (dissolved in a suitable solvent, such as DMSO-saline vehicle) via intraperitoneal injection or oral administration at an appropriate frequency (e.g., once a day). Tumor growth is monitored regularly by methods such as MRI. At the end of the experiment, the mice are sacrificed. The distribution of the drug in the brain and tumors is analyzed by MALDI imaging, and the levels of signaling molecules such as pAKT are detected to evaluate the inhibition of the PI3K pathway. [1] |
| ADME/Pharmacokinetics |
- Distribution：After administration of 15 mg/kg GDC-0084 in rats, the brain-to-plasma total ratio is 1.9 - 3.3. [2]
- Plasma protein binding：In CD-1 mouse plasma, at a concentration of 5 μM, the free fraction is 29.5 ± 2.7% (n = 3), and it binds highly to mouse brain tissues with a free fraction of 6.7% (±1; n = 3). [2] |
| References | |
| Additional Infomation |
- Background and indications：Glioblastoma is the most common primary brain tumor in adults, with over 80% of cases associated with abnormal PI3K signaling. The PI3K pathway is a potential target for the treatment of this disease. GDC-0084 is a PI3K inhibitor specifically optimized to cross the blood-brain barrier and is currently in Phase I clinical trials. [1]
- Mechanism of action：It blocks the PI3K signaling pathway by inhibiting PI3K and mTOR targets, thereby inhibiting the proliferation and survival of tumor cells and exerting antitumor effects. GDC-0084 is under investigation in clinical trial NCT03696355 (Study of GDC-0084 in Pediatric Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma or Diffuse Midline Gliomas). Paxalisib is a phosphatidylinositol 3-kinase (PI3K) inhibitor with potential antineoplastic activity. paxalisib 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. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents. |
| Molecular Formula |
C18H22N8O2
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|---|---|
| Molecular Weight |
382.4197
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| Exact Mass |
382.186
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| Elemental Analysis |
C, 56.53; H, 5.80; N, 29.30; O, 8.37
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| CAS # |
1382979-44-3
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| Related CAS # |
1382979-44-3
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| PubChem CID |
57384863
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| Appearance |
White to off-white solid powder
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| Density |
1.6±0.1 g/cm3
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| Index of Refraction |
1.789
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| LogP |
-0.76
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
28
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| Complexity |
552
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1CCN2C3=C(C(=NC(C4=CN=C(N)N=C4)=N3)N3CCOCC3)N=C2C1(C)C
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| InChi Key |
LGWACEZVCMBSKW-UHFFFAOYSA-N
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| 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)
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| Chemical Name |
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl)pyrimidin-2-amine
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| Synonyms |
Paxalisib; RG 7666; RG7666; RG-7666; GDC0084; Paxalisib [USAN]; 5-(6,6-dimethyl-4-morpholin-4-yl-8,9-dihydropurino[8,9-c][1,4]oxazin-2-yl)pyrimidin-2-amine; 5-(6,6-Dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl)pyrimidin-2-amine; CHEMBL3813842; GDC-0084; GDC 0084
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: ~8 mg/mL (~20.9 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| 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. |
Effect of 16 on the PD marker pAKT in the U87 MG/M human glioblastoma xenograft model after 24 days of continuous dosing.
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COA
Synthetic Route to Obtain Tricyclic Purine-Based Brain Penetrant PI3K Inhibitor16.