1. PI3K/Akt/mTOR
    Autophagy
  2. mTOR
    Autophagy
  3. GDC-0349

GDC-0349 

Cat. No.: HY-15248 Purity: 98.20%
Handling Instructions

GDC-0349 is a potent and selective ATP-competitive mTOR inhibitor with a Ki of 3.8 nM. GDC-0349 inhibits of both mTORC1 and mTORC2 complexes.

For research use only. We do not sell to patients.

GDC-0349 Chemical Structure

GDC-0349 Chemical Structure

CAS No. : 1207360-89-1

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Free Sample (0.5-1 mg)   Apply now  
10 mM * 1 mL in DMSO USD 145 In-stock
Estimated Time of Arrival: December 31
5 mg USD 132 In-stock
Estimated Time of Arrival: December 31
10 mg USD 216 In-stock
Estimated Time of Arrival: December 31
50 mg USD 948 In-stock
Estimated Time of Arrival: December 31
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Customer Review

Based on 1 publication(s) in Google Scholar

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Description

GDC-0349 is a potent and selective ATP-competitive mTOR inhibitor with a Ki of 3.8 nM. GDC-0349 inhibits of both mTORC1 and mTORC2 complexes.

IC50 & Target[1]

mTOR

3.8 nM (Ki)

mTORC1

 

mTORC2

 

Autophagy

 

In Vitro

GDC-0349 (Compound 8h) is a remarkably selective mTOR inhibitor, with less than 25% inhibition of 266 kinases, including all isoforms of PI3K when tested at 1 μM[1].

In Vivo

When dosed orally once daily in athymic mice in a MCF7-neo/Her2 tumor xenograft model (PI3K mutation), GDC-0349 (Compound 8h) inhibits tumor growth in a dose-dependent manner, achieving stasis (99% TGI) at the maximum tolerated dose. Body weight change is less than 10% up to the highest dose. GDC-0349 is also efficacious in other xenograft models, including PC3 (PTEN null) and 786-0 (VHL mutant). Similar levels of tumor growth inhibition are achieved when GDC-0349 is administered once every three days at higher doses compared to once every day. GDC-0349 has ~10-fold reduced free plasma clearance in both mice (100 mL/min/kg) and rats (171 mL/min/kg in rat)[1].

Clinical Trial
Molecular Weight

452.55

Formula

C₂₄H₃₂N₆O₃

CAS No.

1207360-89-1

SMILES

O=C(NCC)NC(C=C1)=CC=C1C2=NC3=C(CCN(C4COC4)C3)C(N5[[email protected]@H](C)COCC5)=N2

Shipping

Room temperature in continental US; may vary elsewhere.

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : ≥ 100 mg/mL (220.97 mM)

*"≥" means soluble, but saturation unknown.

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 2.2097 mL 11.0485 mL 22.0970 mL
5 mM 0.4419 mL 2.2097 mL 4.4194 mL
10 mM 0.2210 mL 1.1049 mL 2.2097 mL
*Please refer to the solubility information to select the appropriate solvent.
In Vivo:
  • 1.

    Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% saline

    Solubility: ≥ 2.5 mg/mL (5.52 mM); Clear solution

  • 2.

    Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in saline)

    Solubility: ≥ 2.5 mg/mL (5.52 mM); Clear solution

  • 3.

    Add each solvent one by one:  10% DMSO    90% corn oil

    Solubility: ≥ 2.5 mg/mL (5.52 mM); Clear solution

*All of the co-solvents are provided by MCE.
References
Kinase Assay
[1]

The kinase activity of mTOR enzyme is assessed by incubating purified recombinant enzyme (mTOR(1360-2549)+GBL, prepared in-house) in a reaction mixture containing ATP, MnCl2, and a fluorescently labeled mTOR substrate, e.g., GFP-4E-BP1. The reaction is stopped by an addition of a Terbium-labeled phospho-specific antibody, e.g., Tb-labeled anti-p4E-BP1 T37/T46, EDTA, and TR-FRET buffer solution. Product formation is detected by way of time-resolved fluorescence resonance energy transfer (TR-FRET), which occurs when the phosphorylated substrate and labeled antibody are in close proximity due to phosphospecific binding. Enzymatic activity is measured as an increase in TR-FRET signal using a Perkin Elmer Envision plate reader. The assay is performed in a 384-well Proxiplate Plus using the following protocol: Compound activity is tested in 10 point dose curves starting at the highest final concentration of 10 uM. They are serially diluted in 100% DMSO prior to further dilution with assay buffer. The reaction mixture (8μL) containing 0.25 nM mTOR+GBL enzyme, 400 nM GFP-4E-BP1, 8 uM ATP, 50 mM Hepes pH 7.5, 0.01% Tween 20, 10 mM MnCl2, 1 mM EGTA, 1 mM DTT, 1% DMSO (±compound) is incubated at room temperature for 30 minutes. 8 μL of solution containing 2 nM Tb-anti-p4E-BP1 antibody & 10 mM EDTA diluted TR-FRET buffer is then added and incubated for 30 minutes to stop the reaction. The plate is scanned with the Envision plate reader. Ki values are calculated in Assay Explorer using the Morrison ATP-competitive tight binding equation for Ki apparent determination[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

Mice[1]
Human breast cancer cells (MCF7 neo/HER2; modified ATCC variant) are implanted subcutaneously into the mammary fat pad of female NCR nude mice (5×106 cells/100 uL of 1:1 mixture of Hank’s Balanced Salt Solution (HBSS)/Matrigel). To support estrogen dependent growth, recipient animals are pre-implanted with 0.36 mg estrogen pellets. Tumors are monitored until they reached a mean tumor volume of approximately 200-225 mm3, then similarly sized tumors are randomly assigned to treatment cohorts (n=5-10). Human 786-O renal adenocarcinoma cells are implanted subcutaneously into the right hind flank of female nu/nu mice (1×107 cells/200 uL in 1:1 PBS/Matrigel). Tumors are monitored until they reached a mean tumor volume of approximately 205 mm3, then similarly sized tumors are randomly assigned to treatment cohorts (n=10). Human prostate cancer NCI-PC3 cells are resuspended in Hank’s Balanced Salt Solution and implanted subcutaneously into the right hind flanks of 120 female NCR nude mice. Each mouse is injected with 5×106 cells. Tumors are monitored until they reached a mean tumor volume of approximately 200-250 mm3. The dimesylate salt of GDC-0349 is dosed daily or every third day by oral gavage (100 uL dose /25 gm animal) for 14-21 days.Tumor volume and body weight measurements are collected twice weekly. Tumor volumes are calculated.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References

Purity: 98.20%

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Keywords:

GDC-0349GDC0349GDC 0349mTORAutophagyMammalian target of RapamycinInhibitorinhibitorinhibit

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GDC-0349
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