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    GDC-0349 (RG7603)
    GDC-0349 (RG7603)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0205
    CAS #: 1207360-89-1Purity ≥98%

    Description: 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. It inhibits mTOR with a Ki of 3.8 nM, and exhibits 790-fold higher selectivity over PI3Kα and other 266 kinases. GDC-0349 showed potent antiproliferative activity in vitro and high antitumor efficacy in vivo. GDC-0349 inhibited tumor growth dose-dependently in athymic mice in a MCF7-neo/Her2 tumor xenograft model.  GDC-0349 was developed by GeneTech for treatment of locally advanced or metastatic solid tumors or non Hodgkin's lymphoma.

    References:J Med Chem. 2013 Apr 11;56(7):3090-101; ACS Med Chem Lett. 2012 Nov 29;4(1):103-7.  

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    Molecular Weight (MW)

    452.55

    Formula

    C24H32N6O3

    CAS No.

    1207360-89-1

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 91 mg/mL (201.1 mM)

    Water: <1 mg/mL

    Ethanol: 6 mg/mL (13.3 mM)

    Other info

    Chemical Name: (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea
    InChi Key: RGJOJUGRHPQXGF-INIZCTEOSA-N
    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
    SMILES Code: O=C(NC1=CC=C(C2=NC(N3[[email protected]@H](C)COCC3)=C4C(CN(C5COC5)CC4)=N2)C=C1)NCC

    Synonyms

    RG-7603; RG7603; RG 7603; GDC0349; GDC 0349; GDC-0349


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    In Vitro

    Kinase Assay: 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 Kiapparent determination.

     

    Cell Assay: GDC-0349 has remarkable selectivity over 266 kinases, including all isoforms of PI3K. GDC-0349 inhibits downstream markers of mTOR, including phospho-4EBP1 and phospho-Akt(S473) in an in vivo PK/PD study in mouse, consistent with an inhibition of both mTORC1 and mTORC2 complexes.

    In Vivo

    GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models. When dosed orally once daily in athymic mice in a MCF7-neo/Her2 tumor xenograft model (PI3K mutation), GDC-0349 inhibits tumor growth in a dose-dependent manner. It is also efficacious in other xenograft models, including PC3 (PTEN null) and 786-O (VHL mutant).

    Animal model

    MCF7-neo/Her2 tumor xenograft

    Formulation & Dosage

    Formulated in 0.5% methylcellulose/0.2% Tween 80; 10, 20, 30, 40,50, 60, 70, 80 mg/kg; p.o.

    References

    J Med Chem. 2013 Apr 11;56(7):3090-101.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    GDC-0349

    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.  2012 Nov 29;4(1):103-7.

    GDC-0349
    Dose-dependent tumor growth inhibition by compound 8h dosed 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.  2012 Nov 29;4(1):103-7.




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