Paxalisib (GDC-0084)

Catalog No.S8163 Synonyms: RG7666

For research use only.

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.

Paxalisib (GDC-0084) Chemical Structure

CAS No. 1382979-44-3

Selleck's Paxalisib (GDC-0084) has been cited by 1 Publication

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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 Research:[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 1.3×105 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 (Papp), in the apical to A-B and B-A directions, is calculated after 2-hour incubation.
Animal Research:[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.

Solubility (25°C)

In vitro

Chemical Information

Molecular Weight 382.42
Formula

C18H22N8O2

CAS No. 1382979-44-3
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC1(C2=NC3=C(N2CCO1)N=C(N=C3N4CCOCC4)C5=CN=C(N=C5)N)C

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT05012670 Active not recruiting Drug: [14C]-Paxalisib Capsule Healthy Kazia Therapeutics Limited|Quotient Sciences August 18 2021 Phase 1
NCT03696355 Active not recruiting Drug: GDC-0084|Radiation: radiation therapy Brain and Central Nervous System Tumors St. Jude Children''s Research Hospital|Kazia Therapeutics Limited November 19 2018 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-08-01)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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