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Vismodegib

Catalog No. T2590   CAS 879085-55-9
Synonyms: Erivedge, GDC-0449, RG 3616

Vismodegib (GDC-0449) is a hedgehog pathway inhibitor (IC50: 3 nM). It also inhibits P-gp (IC50: 3.0 μM), ABCG2 (IC50: 1.4 μM).

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Vismodegib Chemical Structure
Vismodegib, CAS 879085-55-9
Pack Size Availability Price/USD Quantity
5 mg In stock $ 38.00
10 mg In stock $ 53.00
50 mg In stock $ 67.00
100 mg In stock $ 85.00
200 mg In stock $ 110.00
1 mL * 10 mM (in DMSO) In stock $ 57.00
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Purity: 99.99%
Purity: 99.04%
Purity: 98.98%
Purity: 98%
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Biological Description
Chemical Properties
Storage & Solubility Information
Description Vismodegib (GDC-0449) is a hedgehog pathway inhibitor (IC50: 3 nM). It also inhibits P-gp (IC50: 3.0 μM), ABCG2 (IC50: 1.4 μM).
Targets&IC50 ABCG2:1.4 μM, P-gp:3.0 μM, Hedgehog:3 nM (cell free)
In vitro Vismodegib (GDC-0449) is a potent inhibitor of two ABC transporters, ABCG2/BCRP and ABCB1/Pgp, and is a mild inhibitor of ABCC1/MRP1. In ABCG2-overexpressing HEK293 cells, Vismodegib increased retention of the fluorescent ABCG2 substrate BODIPY-prazosin and resensitized these cells to mitoxantrone, an antineoplastic ABCG2 substrate. Vismodegib also resensitized 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 IC(50) values of Vismodegib for inhibition of ABCG2 and Pgp were approximately 1.4 and approximately 3.0 μM, respectively [2]. GDC-0449 inhibited cell growth in cisplatin-na?ve and -resistant cells. In both cell types, GDC-0449 increased [Ca(2+)](cyto) and reduced endoplasmatic [Ca(2+)](ER) [3].
In vivo Oral dosing of vismodegib caused 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 CRC models, D5123, and 1040830. Analysis of Hh pathway activity and PK/PD modeling reveals that vismodegib inhibits Gli1 with a similar IC(50) in both the medulloblastoma and D5123 models (0.165 μmol/L ±11.5% and 0.267 μmol/L ±4.83%, respectively). Pathway modulation was linked to efficacy using an integrated PK/PD model revealing a steep relationship where > 50% of the activity of vismodegib is associated with >80% repression of the Hh pathway [4].
Cell Research MDCKII cells were plated into 24-well plates at a density of 3 x 10^5 cells per well and were allowed to attach. The medium was then changed to that containing different drugs (50 μM VP, 50 μM indomethacin, or 20 μM Vismodegib) in DMSO or DMSO alone as control, and nonfluorescent calcein-AM was added to a final concentration of 1.0 μM and incubated at 37°C for 2 hours. Cells were 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 was then transferred into 96-well plates, and the fluorescence signal caused by the cell-derived calcein was quantified spectrophotometrically with a SpectraMax M5 Multi-Detection Reader using an excitation wavelength of 495 nm and an emission wavelength of 515 nm. All manipulations were performed in the dark. All readings are expressed as mean ± SEM normalized to the control [2].
Animal Research Female CD-1 nude mice (weighing 25–28 g) were administered oral doses of 5, 15, 50, and 100 mg/kg (free base equivalent) of vismodegib hydrochloride salt in 0.5% methylcellulose/0.2% Tween 80 (MCT). Blood samples (~1 mL) were collected up to 24 hours postdose via cardiac puncture (terminal collection) into tubes containing potassium ethylenediaminetetraacetic acid (K2EDTA) anticoagulant. Immediately on the collection, the blood was mixed with K2EDTA and stored on ice. Within 30 minutes, blood samples were centrifuged at approximately 1000 to 1500 × g for 5 minutes at 4°C, and plasma was harvested. The plasma samples were stored at ?80°C until analysis. Concentrations of vismodegib were determined by LC/MS/MS as described previously [4].
Synonyms Erivedge, GDC-0449, RG 3616
Molecular Weight 421.3
Formula C19H14Cl2N2O3S
CAS No. 879085-55-9

Storage

Powder: -20°C for 3 years | In solvent: -80°C for 1 year

Solubility Information

DMSO: 78 mg/mL (185.1 mM)

Ethanol: Insoluble

H2O: Insoluble

TargetMolReferences and Literature

1. Scales SJ, et al. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009 Jun;30(6):303-12. 2. Zhang Y, et al. Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp. Neoplasia. 2009 Jan;11(1):96-101. 3. Tian F, et al. The hedgehog pathway inhibitor GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells. Anticancer Res. 2012 Jan;32(1):89-94. 4. Wong H, et al. Pharmacokinetic-pharmacodynamic analysis of vismodegib in preclinical models of mutational and ligand-dependent Hedgehog pathway activation. Clin Cancer Res. 2011 Jul 15;17(14):4682-92.

TargetMolCitations

1. Hu A, Zhang J Z, Wang J, et al. Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate. Cell Research. 2022, 32(3): 288-301. 2. Wu Q, Huang Q, Jiang Y, et al. Remodeling Chondroitin-6-Sulfate–Mediated Immune Exclusion Enhances Anti–PD-1 Response in Colorectal Cancer with Microsatellite Stability. Cancer Immunology Research. 2021 3. Wu Q, Huang Q, Jiang Y, et al. Remodeling Chondroitin-6-Sulfate–Mediated Immune Exclusion Enhances Anti–PD-1 Response in Colorectal Cancer with Microsatellite Stability. Cancer Immunology Research. 2021 4. Wu H, Zhang L, Chen B, et al.B13, a well-tolerated inhibitor of hedgehog pathway, exhibited potent anti-tumor effects against colorectal carcinoma in vitro and in vivo.Bioorganic Chemistry.2023: 106488.

Related compound libraries

This product is contained In the following compound libraries:
Anti-Cancer Active Compound Library Anti-Cancer Clinical Compound Library Anti-Cancer Approved Drug Library Anti-Cancer Drug Library Anti-Obesity Compound Library FDA-Approved & Pharmacopeia Drug Library Target-Focused Phenotypic Screening Library Drug-induced Liver Injury (DILI) Compound Library Clinical Compound Library Anti-Lung Cancer Compound Library

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Keywords

Vismodegib 879085-55-9 Autophagy GPCR/G Protein Membrane transporter/Ion channel Stem Cells Hedgehog/Smoothened ABC GDC0449 Hedgehog Inhibitor RG3616 inhibit Erivedge RG-3616 GDC-0449 RG 3616 GDC 0449 inhibitor

 

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