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    Vismodegib (GDC-0449)
    Vismodegib (GDC-0449)

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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 #: V1331
    CAS #: 879085-55-9Purity ≥98%

    Description: Vismodegib (formerly known as GDC-0449; RG-3616; GDC0449; RG3616; trade name: Erivedge) is a potent, orally bioavailable, first-in-class and specific hedgehog pathway inhibitor with potential anticancer activity. It was approved in 2012 by the USA FDA as an anticancer drug for the treatment of basal-cell carcinoma. Vismodegib inhibits hedgehog with IC50 of 3 nM and also inhibits P-gp with IC50 of 3.0 μM in a cell-free assay. Vismodegib targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. Vismodegib was approved by in January, 2012. As the first-in-class orally-administered small molecule which is designed to selectively inhibit the Hedgehog signaling pathway by targeting a protein called Smoothened, Genetic mutations that lead to unregulated activation of Hedgehog signaling are found in basal cell carcinoma (BCC) and medulloblastomas. Aberrant signaling in the Hedgehog pathway is implicated in over 90% of BCC cases.

    References: Neoplasia. 2009 Jan;11(1):96-101; Clin Cancer Res. 2011 Jul 15;17(14):4682-92.

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    Molecular Weight (MW)421.3
    FormulaC19H14Cl2N2O3S
    CAS No.879085-55-9
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 84 mg/mL (199.4 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 10mg/mL  
    SynonymsRG3616; GDC0449; RG 3616; GDC 0449; RG-3616; GDC-0449; trade name: Erivedge


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    In Vitro

    In vitro activity: GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. GDC-0449 prevents multiple ATP-binding cassette (ABC) transporters. GDC-0449 also blocks ABCG2, Pgp, and MRP1-important ABC transporters associated with MDR. GDC-0449 is a potent inhibitor of ABC transporters, ABCG2/BCRP and ABCB1/Pgp, and is a mild inhibitor of ABCC1/MRP1. In ABCG2-overexpressing HEK293 cells, GDC-0449 increases retention of the fluorescent ABCG2 substrate BODIPY-prazosin and resensitizes these cells to mitoxantrone. In Madin-Darby canine kidney II cells engineered to overexpress Pgp or MRP1, GDC-0449 increases the retention of calcein-AM and resensitizes them to colchicine. GDC-0449 also resensitizes human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to mitoxantrone, to mitoxantrone, and to topotecan or SN-38. The IC50 values of GDC-0449 for prevention of ABCG2 and Pgp are about 1.4 μM and 3.0 μM, respectively. GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells.


    Kinase Assay: Vismodegib (GDC-0449) is an orally active hedgehog pathway inhibitor with an IC50 of 3 nM. It also inhibits P-gp, ABCG2 with IC50 values of 3.0 μM and 1.4 μM, respectively.


    Cell Assay: MDCKII cells are seeded into 24-well plates at a density of 3 × 105 cells per well and are allowed to attach. Medium is then changed to that containing different drugs (50 μM VP, 50 μM indomethacin, or 20 μM GDC-0449 in DMSO or DMSO alone as control, and nonfluorescent calcein-AM is added to a final concentration of 1.0 μM and incubated at 37 °C for 2 hours. Cells are then washed twice with Ca2+, Mg2+-containing Hank's balanced salt solution buffer and lysed by shaking in 0.01% Triton X-100 in PBS buffer for 1 hour at room temperature or overnight at 4 °C. The lysate is then transferred into 96-well plates, and the fluorescence signal caused by the cell-derived calcein is quantified spectrophotometrically with a SpectraMax M5 Multi-Detection Readerusing an excitation wavelength of 495 nm and an emission wavelength of 515 nm. All manipulations are performed in the dark. All readings are expressed as mean ?SEM normalized to the control.

    In VivoGDC-0449 has been used to treat medulloblastoma in animal models. GDC-0449 prevents the growth of primary pancreatic xenografts without non-specifically inhibiting pancreatic cell proliferation. Oral dosing of GDC-0449 causes tumor regressions in the Ptch(+/-) allograft model of medulloblastoma at doses ≥25 mg/kg and tumor growth inhibition at doses up to 92 mg/kg dosed twice daily in two ligand-dependent colorectal cancer models, D5123, and 1040830. Analysis of Hh pathway activity and PK/PD modeling reveals that GDC-0449 inhibits Gli1 with a similar IC50 in both the medulloblastoma and D5123 models (0.165 μM and 0.267 μM, respectively). Pathway modulation is linked to efficacy using an integrated PK/PD model revealing a steep relationship where > 50% of the activity of GDC-0449 is associated with >80% repression of the Hh pathway.
    Animal modelPtch(+/-) allograft model, D5123 and 1040830
    Formulation & DosageDissolved in  0.5% methyl-cellulose, 0.2% tween-80; 100 mg/kg; oral gavage
    ReferencesNeoplasia. 2009 Jan;11(1):96-101; Clin Cancer Res. 2011 Jul 15;17(14):4682-92.


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

     

    Vismodegib (GDC-0449)

     

    Vismodegib (GDC-0449)

    Neoplasia. 2009 Jan;11(1):96-101.
     

    Vismodegib (GDC-0449)

    HhAntag691 (Vismodegib (GDC-0449)), 10 µM, resensitizes MDCKII/Pgp cells and MDCKII/MRP1 cells to colchicine treatment. Neoplasia. 2009 Jan;11(1):96-101.


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