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Vismodegib(GDC-0449)
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
Vismodegib(GDC-0449)图片
CAS NO:879085-55-9
规格:≥98%
包装与价格:
包装价格(元)
100mg电议
250mg电议
500mg电议
1g电议
2g电议

产品介绍
理化性质和储存条件
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
实验参考方法
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.