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Chemical Structure| 1382979-44-3 Chemical Structure| 1382979-44-3

Structure of GDC-0084
CAS No.: 1382979-44-3

Chemical Structure| 1382979-44-3

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GDC-0084 is a brain penetrant inhibitor of PI3K and mTOR.

Synonyms: Paxalisib; RG7666

4.5 *For Research Use Only !

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Product Citations

Product Citations

Guo, Tongxuan ; Wu, Changyong ; Zhang, Junhao ; Yu, Jiefeng ; Li, Guoxi ; Jiang, Hongyan , et al.

Abstract: Background: Glioblastoma multiforme (GBM) is a devastating disease that lacks efective drugs for targeted therapy. Previously, we found that the third-generation epidermal growth factor receptor (EGFR) inhibitor AZD-9291 persistently blocked the activation of the ERK pathway but had no inhibitory efect on the phosphoinositide 3-kinase (PI3K)/Akt pathway. Given that the PI3K inhibitor GDC-0084 is being evaluated in phase I/II clinical trials of GBM treatment, we hypothesized that combined inhibition of the EGFR/ERK and PI3K/Akt pathways may have a synergistic efect in the treatment of GBM. Methods: The synergistic efects of cotreatment with AZD-9291 and GDC-0084 were validated using cell viability assays in GBM and primary GBM cell lines. Moreover, the underlying inhibitory mechanisms were assessed through colony formation, EdU proliferation, and cell cycle assays, as well as RNA-seq analyses and western blot. The therapeutic efects of the drug combination on tumor growth and survival were investigated in mice bearing tumors using subcutaneously or intracranially injected LN229 xenografts. Results: Combined treatment with AZD-9291 and GDC-0084 synergistically inhibited the proliferation and clonogenic survival, as well as induced cell cycle arrest of GBM cells and primary GBM cells, compared to monotherapy. Moreover, AZD-9291 plus GDC-0084 combination therapy signifcantly inhibited the growth of subcutaneous tumors and orthotopic brain tumor xenografts, thus prolonging the survival of tumor-bearing mice. More importantly, the combination of AZD-9291 and GDC-0084 simultaneously blocked the activation of the EGFR/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby exerting signifcant antitumor activity. Conclusion: Our fndings demonstrate that the combined blockade of the EGFR/MEK/ERK and PI3K/AKT/mTOR pathways is more efective against GBM than inhibition of each pathway alone, both in vitro and in vivo. Our results suggest that AZD-9291 combined with GDC-0084 may be considered as a potential treatment strategy in future clinical trials.

Keywords: Glioblastoma ; AZD-9291 ; GDC-0084 ; Combination therapy ; Synergistic inhibition

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Product Details of GDC-0084

CAS No. :1382979-44-3
Formula : C18H22N8O2
M.W : 382.42
SMILES Code : NC1=NC=C(C2=NC(N3CCOCC3)=C4N=C(C(C)(C)OCC5)N5C4=N2)C=N1
Synonyms :
Paxalisib; RG7666
MDL No. :MFCD30187522
InChI Key :LGWACEZVCMBSKW-UHFFFAOYSA-N
Pubchem ID :57384863

Safety of GDC-0084

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Related Pathways of GDC-0084

PI3K-AKT

Isoform Comparison

Biological Activity

Target
  • p110γ

    PI3Kγ, Ki app:10 nM

  • p110β

    PI3Kβ, Ki app:46 nM

  • p110α

    PI3Kα, Ki app:2 nM

  • p110δ

    PI3Kδ, Ki app:3 nM

In Vitro:

Cell Line
Concentration Treated Time Description References
GBM cell lines (G111, G96, G112, U87, SF268, G122) 0.27-1.01 µM (EC50) 4 days Evaluate the antiproliferative effect of GDC-0084 in multiple GBM cell lines, EC50 range from 0.27 to 1.01 μM ACS Med Chem Lett. 2016 Feb 16;7(4):351-6.
Acanthamoeba castellanii 18 µM 48 hours Evaluate the inhibitory effect of GDC-0084 on Acanthamoeba castellanii, showing an EC50 of 18 μM. Int J Parasitol Drugs Drug Resist. 2019 Dec;11:80-94.
Naegleria fowleri 3.7 µM (EC50) 48 hours Evaluate the inhibitory effect of GDC-0084 on Naegleria fowleri, showing an EC50 of 3.7 μM. Int J Parasitol Drugs Drug Resist. 2019 Dec;11:80-94.
Balamuthia mandrillaris 3.7 µM (EC50) 72 hours Evaluate the inhibitory effect of GDC-0084 on Balamuthia mandrillaris, showing an EC50 of 3.7 μM. Int J Parasitol Drugs Drug Resist. 2019 Dec;11:80-94.
PC3 cells 0.4 µM Evaluate the antiproliferative effect of GDC-0084 in PC3 cells, EC50 of 0.4 μM ACS Med Chem Lett. 2016 Feb 16;7(4):351-6.

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
NCT01547546 Glioblastoma, Glioma PHASE1 COMPLETED 2025-01-15 Los Angeles, California, 90095... More >>, United States|Boston, Massachusetts, 02114, United States|Boston, Massachusetts, 02115, United States|Houston, Texas, 77030, United States|Barcelona, 08035, Spain Less <<

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.61mL

0.52mL

0.26mL

13.07mL

2.61mL

1.31mL

26.15mL

5.23mL

2.61mL

Dissolving Methods
Please choose the appropriate dissolution scheme according to your animal administration guide.For the following dissolution schemes, clear stock solution should be prepared according to in vitro experiments, and then cosolvent should be added in turn:

in order to ensure the reliability of the experimental results, the clarified stock solution can be properly preserved according to the storage conditions; The working fluid for in vivo experiment is recommended to be prepared now and used on the same day;

The percentage shown in front of the following solvent refers to the volume ratio of the solvent in the final solution; If precipitation or precipitation occurs in the preparation process, it can be assisted by heating and/or ultrasound.
Protocol 1
Protocol 2

References

 

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