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    RO4929097 (RO4929097; R4733; RO04929097)
    RO4929097 (RO4929097; R4733; RO04929097)

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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 #: V0715
    CAS #: 847925-91-1Purity ≥98%

    Description: RO4929097 (also called RO-4929097; RO04929097; R-4733) is a novel, potent and orally bioavailable small molecule inhibitor of the γ-secretase (gamma secretase-GS) with potential antitumor activity. It inhibits γ-secretase with an IC50 of 4 nM in a cell-free assay and also inhibits cellular processing of Aβ40 and Notch (substrate for γ-secretase) with EC50s of 14 nM and 5 nM, respectively. RO4929097 binds to GS and blocks activation of Notch receptors, which may inhibit tumor cell proliferation. Since overexpression of the Notch signaling pathway has been correlated with increased tumor cell growth, RO4929097 has the potential to treat cancer. The integral membrane protein GS is a multi-subunit protease complex that cleaves single-pass transmembrane proteins, such as Notch receptors, at residues within their transmembrane domains. 

    References: Cancer Res. 2009 Oct 1;69(19):7672-80; Breast Cancer Res Treat. 2012 Jul;134(2):495-510.

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    Molecular Weight (MW)469.4
    FormulaC22H20F5N3O3
    CAS No.847925-91-1
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 94 mg/mL (200.3 mM)
    Water: <1 mg/mL
    Ethanol: 16 mg/mL (34.1 mM)
    Solubility (In vivo)2% DMSO+30% PEG 300+5% Tween+ddH2O: 10 mg/mL
    SynonymsRO4929097; RO-4929097; RO 4929097; RO04929097; RO-04929097; RO 04929097; R4733; R 4733; R-4733;
    Chemical Name(S)-2,2-dimethyl-N1-(6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N3-(2,2,3,3,3-pentafluoropropyl) malonamide
    SMILES CodeO=C(N[[email protected]]1C2=CC=CC=C2C3=CC=CC=C3NC1=O)C(C)(C)C(NCC(F)(F)C(F)(F)F)=O


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    In Vitro

    In vitro activity: RO4929097 decreases the amount of Aβ peptides secreted into the culture medium in HEK293 cells with EC50 of 14 nM. RO4929097 strongly inhibits Notch processing with EC50 of 5 nM in the Notch cell-based reporter assay. The potency of RO4929097 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity observed with respect to 75 other proteins of various types including receptors, ion channels, and enzymes (CEREP panel). After 5 days of treatment, RO4929097 reduces the production of ICN in the human NSCLC A549 cells inducing a flattened and less transformed tumor cell phenotype in tissue culture. RO4929097 blocks Notch processing in human non-small cell lung carcinoma cells and decreases expression of the Notch transcriptional target gene Hes1. Treatment with RO4929097 reveals a two- to threefold decrease in the expression of direct Notch target genes, Hes1, Hey1, and Heyl in SUM149 and a 3.5- to eightfold decrease in expression in SUM190 cells. RO4929097 modestly inhibits the growth of SUM149 cells in a dose-dependent manner. At a concentration of 1 μM of RO4929097, growth inhibition is 20 % for SUM149 and 10 % for SUM190 cells, relative to vehicle-treated controls. RO4929097 decreases the production of inflammatory cytokines by T-cells. Furthermore, with RO4929097 treatment, there is a shift in favor of TH2 over TH1 cytokines. In addition, T-cell activation induced IL-6 production would be increased with RO4929097. Upon RO4929097 treatment, the selected melanoma cell lines reveals downregulation of NOTCH downstream effector HES1. A decrease in the amount of melanospheres formed upon RO4929097 treatment in primary melanoma cell lines is detected.


    Kinase Assay: After RO4929097 is used, the Aβ peptides are measured by ECL assays using a variety of anti-Aβ antibodies and an Origen 1.5 Analyzer. The 4G8 murine mAb binds an epitope in the Aβ peptide (within amino acids 18–21) that is immediately distal to the α-secretase cleavage site. The G2–10 murine mAb binds the C terminus that is exposed after γ-secretase-mediated cleavage to generate amino acid 40 of the Aβ40 peptide. The FCA3542 rabbit antibody binds the C terminus that is exposed after γ-secretase-mediated cleavage to generate amino acid 42 of the Aβ42 peptide. The 4G8 mAb is biotinylated with biotin-LC-sulfo-N-hydroxysuccinimide-ester. The G2–10 and FCA3542 antibodies are ruthenylated with TAG-N-hydroxysuccinimide ester. Aβ(x-40) is detected with biotinylated 4G8 and ruthenylated G2–10. Aβ(x-42) is detected with biotinylated 4G8 and ruthenylated FCA3542.


    Cell Assay: Primary melanoma cell lines, including WM35 and WM98.1, are seeded at 2.5 × 103 cells per well on a 12-well dish in triplicate. The day after (day 0), the medium is replaced, and DMSO or 10 μM RO4929097 is added and changed every 3-4 days. At the indicated time points, cells are fixed in 10% formalin solution and stored in PBS at 4 °C. At day 18-24, all the plates are stained with crystal violet. After color elution with 10% acetic acid, optical density is read at 590 nm.

    In VivoOral injection of 3 to 60 mg/kg RO4929097 once daily or twice daily to nude mice bearing A549 NSCLC xenografts for either 7, 14, or 21 days of a 21-day schedule results in significant tumor growth inhibition compared with vehicle-treated animals. The tumor growth inhibition values ranges from 66% to 91%. When mice are treated with 60 mg/kg RO4929097 twice daily with the 7+/14- schedule, treatment initially arouses regression of established A549 tumors. At the end of the 21-day cycle (day 47), tumor growth prevention is still 91% compared with vehicle control mice. Inhibition of tumor growth remains prolonged and sustained up to 34 days post-treatment (day 67). On day 67, these mice are retreated with the same dose of RO4929097 for a second cycle (7 days) until day 74. Importantly, the antitumor effects are sustained after dosing is completed. RO4929097 leads to reduced expression of genes associated with angiogenesis in A549 xenograft model. In contrast, the RO4929097-resistant H460a xenograft displays little change in expression of these genes, underscoring the in vivo anti-angiogenesis mechanism of action of RO4929097. For IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts.
    Animal modelFemale nude mice bearing Calu-6 cells
    Formulation & DosageDissolved in 1.0% Klucel in water with 0.2% Tween 80;  3 to 60 mg/kg; Oral gavage
    References

    Cancer Res. 2009 Oct 1;69(19):7672-80; Breast Cancer Res Treat. 2012 Jul;134(2):495-510.


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

    • Batch #: V071502,Purity ≥98%

    • COA
     

    RO4929097

     
    RO4929097
    RO4929097 inhibits the production of ICN, reducing the expression of the downstream Notch target Hes1, producing a less transformed morphology in A549 cells. Cancer Res. 2009 Oct 1;69(19):7672-80. 
     
    RO4929097
    In vivo efficacy of RO4929097 in the A549 xenograft model. Cancer Res. 2009 Oct 1;69(19):7672-80. 
    RO4929097
    RO4929097-treated A549 tumors have increased areas of necrosis with relative increase in extracellular matrix (ECM). Cancer Res. 2009 Oct 1;69(19):7672-80.
     
    RO4929097
    Hes1 mRNA can serve as a pharmacodynamic marker for tracking Notch inhibition in hair follicles. Cancer Res. 2009 Oct 1;69(19):7672-80. 
     
    RO4929097
    Comparative microarray analysis. A, heat map of human gene expression changes induced by RO4929097 at 6 and 24 h in A549. Cancer Res. 2009 Oct 1;69(19):7672-80. 


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