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Purity: ≥98%
GDC-0349(also known as RG-7603) is a novel, potent, orally bioavailable and selective ATP-competitive inhibitor of mTOR (mammalian target of rapamycin) with potential antitumor activity. With a Ki of 3.8 nM and 790-fold higher selectivity over PI3K and the other 266 kinases, it inhibits mTOR. High antitumor efficacy and potent antiproliferative activity were demonstrated by GDC-0349 in vivo. In an MCF7-neo/Her2 tumor xenograft model, GDC-0349 dose-dependently slowed the growth of tumors in athymic mice. GeneTech created GDC-0349 to treat non-Hodgkin lymphoma as well as locally or metastatic advanced solid tumors.
| Targets |
mTOR (Ki = 3.8 nM); PI3Kα (Ki = 3 μM); mTORC1; mTORC2; Autophagy
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| ln Vitro |
GDC-0349 has remarkable selectivity over 266 kinases, including all isoforms of PI3K.[1] In an in vivo PK/PD study with mice, GDC-0349 inhibits downstream mTOR markers like phospho-4EBP1 and phospho-Akt(S473), which is consistent with the inhibition of both mTORC1 and mTORC2 complexes.[1]
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| ln Vivo |
GDC-0349 exhibits dose-dependent efficacy and pathway modulation in mouse xenograft cancer models. In an MCF7-neo/Her2 tumor xenograft model in athymic mice (PI3K mutation), GDC-0349 inhibits tumor growth in a dose-dependent manner. Additionally, it works well in other xenograft models like PC3 (PTEN null) and 786-O (VHL mutant). [1]
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| Enzyme Assay |
In order to measure the mTOR enzyme's kinase activity, purified recombinant enzyme (mTOR(1360-2549)+GBL, made in-house) is incubated with ATP, MnCl2, and a fluorescently labeled mTOR substrate, such as GFP-4E-BP1. Addition of a Terbium-labeled phospho-specific antibody, such as Tb-labeled anti-p4E-BP1 T37/T46, EDTA, and TR-FRET buffer solution, stops the reaction. 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. Using a Perkin Elmer Envision plate reader, enzymatic activity is quantified as a rise in TR-FRET signal. The assay is conducted using the following protocol in a 384-well Proxiplate Plus: The 10 point dose curves used to test compound activity start 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].
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| Animal Protocol |
Mice: 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). Animal recipients are pre-implanted with pellets containing 0.36 mg of estrogen to support estrogen-dependent growth. Prior to being randomly assigned to treatment cohorts (n=5–10), tumors are monitored until they reach a mean tumor volume of roughly 200–225 mm3. 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.
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| References | |
| Additional Infomation |
GDC-0349 has been used in trials studying the treatment of Non-Hodgkin's Lymphoma, Solid Tumor.
mTOR Inhibitor GDC-0349 is an orally bioavailable, ATP-competitive, tetrahydroquinazoline (THQ)-based inhibitor of the mammalian target of rapamycin (mTOR) with potential antineoplastic activity. Upon administration, GDC-0349 selectively binds to and inhibits the activity of mTOR, which may result in both the induction of tumor cell apoptosis and a decrease in tumor cell proliferation. mTOR, a serine/threonine kinase belonging to the phosphatidylinositol-3 (PI3K) kinase-related kinase (PIKK) family, plays an important role in the PI3K/Akt/mTOR signaling pathway that regulates cell growth and proliferation, and its expression or activity is frequently dysregulated in human cancers. |
| Molecular Formula |
C24H32N6O3
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|---|---|
| Molecular Weight |
452.54928
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| Exact Mass |
452.253
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| Elemental Analysis |
C, 63.70; H, 7.13; N, 18.57; O, 10.61
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| CAS # |
1207360-89-1
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| Related CAS # |
1207360-89-1
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| PubChem CID |
59239165
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
571.3±50.0 °C at 760 mmHg
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| Flash Point |
299.3±30.1 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.620
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| LogP |
1.04
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
656
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C(NCC)NC(C=C1)=CC=C1C2=NC3=C(CCN(C4COC4)C3)C(N5[C@@H](C)COCC5)=N2
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| InChi Key |
RGJOJUGRHPQXGF-INIZCTEOSA-N
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| InChi Code |
InChI=1S/C24H32N6O3/c1-3-25-24(31)26-18-6-4-17(5-7-18)22-27-21-12-29(19-14-33-15-19)9-8-20(21)23(28-22)30-10-11-32-13-16(30)2/h4-7,16,19H,3,8-15H2,1-2H3,(H2,25,26,31)/t16-/m0/s1
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| Chemical Name |
1-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-7-(oxetan-3-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]phenyl]urea
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| Synonyms |
RG-7603; RG7603; G 7603; GDC0349; GDC 0349; GDC-0349
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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: ~91 mg/mL (~201.1 mM)
Water: <1 mg/mL Ethanol: ~6 mg/mL (~13.3 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.52 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 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 |
*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 |
| NCT01356173 | Completed | Drug: GDC-0349 | Non-Hodgkin's Lymphoma, Solid Tumor |
Genentech, Inc. | June 2011 | Phase 1 |
Combination of mTOR (GDC-0349) or PI3K (GDC-0941) inhibitor with MEK inhibitor GDC-0973 dosed orally QD increases tumor growth inhibition in the A549 mouse xenograft lung cancer model.ACS Med Chem Lett.2012 Nov 29;4(1):103-7. |
 Dose-dependent tumor growth inhibition by compound8hdosed orally in the MCF7-neo/Her-2 mouse xenograft breast cancer model. The dosages from top to bottom are 0 (vehicle), 10, 20, 30, 40, 50, 60, 70, and 80 mg/kg QD, respectively.ACS Med Chem Lett.2012 Nov 29;4(1):103-7. |
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