Paxalisib (GDC-0084)

Catalog No.S8163 Batch:S816302

Technical Data

Formula	C₁₈H₂₂N₈O₂
Molecular Weight	382.42	CAS No.	1382979-44-3
Solubility (25°C)*	In vitro	DMSO	8 mg/mL (20.91 mM)
		Water	Insoluble
		Ethanol	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

Paxalisib (GDC-0084, RG7666) is a brain penetrant inhibitor of PI3K and mTOR with Kiapp values of 2 nM, 46 nM, 3 nM, 10 nM and 70 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ and mTOR.

Targets

PI3Kα ^[1] (Cell-free assay)	PI3Kδ ^[1] (Cell-free assay)	PI3Kγ ^[1] (Cell-free assay)	PI3Kβ ^[1] (Cell-free assay)	mTOR ^[1] (Cell-free assay)
2 nM(Ki app)	3 nM(Ki app)	10 nM(Ki app)	46 nM(Ki app)	70 nM(Ki app)

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^[1]. 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)^[2].

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^[2].

Protocol (from reference)

Cell Assay:^{^[2]}	Cell lines Madin-Darby canine kidney (MDCK) cells （MDR1-MDCKI cells） Concentrations 5 μM Incubation Time 2 h 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 1.3×10_⁵ 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 (P_app), in the apical to A-B and B-A directions, is calculated after 2-hour incubation.
Animal Study:^{^[1]}	Animal Models Male Sprague−Dawley rats or female CD-1 mice Dosages 1 mg/kg（i.v.）;5 or 25 mg/kg(p.o.) Administration i.v. or p.o.

Cell Assay:^{^[2]}

Cell lines
Madin-Darby canine kidney (MDCK) cells （MDR1-MDCKI cells）
Concentrations
5 μM
Incubation Time
2 h
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 1.3×10_⁵ 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 (P_app), in the apical to A-B and B-A directions, is calculated after 2-hour incubation.

Animal Study:^{^[1]}

Animal Models
Male Sprague−Dawley rats or female CD-1 mice
Dosages
1 mg/kg（i.v.）;5 or 25 mg/kg(p.o.)
Administration
i.v. or p.o.

References

Selleck's Paxalisib (GDC-0084) has been cited by 4 publications

Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth [ Cell Death Discov, 2023, 9(1):172]	PubMed: 37202382
Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth [ Cell Death Discov, 2023, 9(1):172]	PubMed: 37202382
Liver Endothelium Promotes HER3-Mediated Cell Survival in Colorectal Cancer with Wild-Type and Mutant KRAS [ Mol Cancer Res, 2022, 20(6):996-1008]	PubMed: 35276002
Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy. [ Cell Stem Cell, 2019, 10.1016/j.stem.2019.10.005]	PubMed: 31786016

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SHIPPING AND STORAGE
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