Vismodegib (GDC-0449)

Alias: RG3616; GDC0449; RG 3616; GDC 0449; RG-3616; GDC-0449; trade name: Erivedge
Cat No.:V1331 Purity: ≥98%
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.
Vismodegib (GDC-0449) Chemical Structure CAS No.: 879085-55-9
Product category: Hedgehog(Smoothened) ROCK
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product 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 given FDA approval in 2012 to treat basal-cell carcinoma as an anticancer medication. In a test conducted without cell culture, vismodegib inhibits hedgehog at an IC50 of 3 nM and P-gp at an IC50 of 3.0 μM. Vismodegib inhibits Hedgehog signaling by blocking the actions of the cell surface receptors PTCH and/or SMO, which are targets of the Hedgehog ligand. In January of 2012, Vismodegib received approval. This novel oral small molecule selectively inhibits the Hedgehog signaling pathway by targeting the Smoothened protein. Genetic mutations causing uncontrolled activation of Hedgehog signaling are present in medulloblastomas and basal cell carcinomas (BCC). More than 90% of BCC cases involve aberrant signaling in the Hedgehog pathway.

Biological Activity I Assay Protocols (From Reference)
Targets
hedgehog ( IC50 = 3 nM ); P-gp ( IC50 = 3.0 μM ); ABCG2 ( IC50 = 1.4 μM )
ln Vitro

In vitro activity: GDC-0449 targets the Hedgehog signaling pathway, suppresses Hedgehog signaling by preventing the Hedgehog-ligand cell surface receptors PTCH and/or SMO from acting. GDC-0449 inhibits multiple transporters of the ATP-binding cassette (ABC). Important ABC transporters linked to MDR, including ABCG2, Pgp, and MRP1, are also blocked by GDC-0449. While mildly inhibiting ABCC1/MRP1, GDC-0449 is a strong inhibitor of ABC transporters, ABCG2/BCRP and ABCB1/Pgp. GDC-0449 increases the retention of the fluorescent ABCG2 substrate BODIPY-prazosin in HEK293 cells that overexpress ABCG2, thereby resensitizing the cells to mitoxantrone. GDC-0449 resensitizes Madin-Darby canine kidney II cells to colchicine and increases the retention of calcein-AM in these cells, which are engineered to overexpress Pgp or MRP1. Additionally, human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to mitoxantrone, topotecan, or SN-38, are sensitized again by GDC-0449. GDC-0449's IC50 values for Pgp and ABCG2 prevention are approximately 3.0 μM and 1.4 μM, respectively.[2] GDC-0449 modifies intracellular Ca2+ homeostasis and suppresses the proliferation of lung cancer cells resistant to cisplatin.[3]

ln Vivo
GDC-0449 has been used to treat medulloblastoma in animal models. [2] GDC-0449 inhibits pancreatic cell proliferation without selectively halting the growth of primary pancreatic xenografts. GDC-0449 is administered orally twice daily in two ligand-dependent colorectal cancer models, D5123, and 1040830, resulting in tumor regressions at doses ≥25 mg/kg in the Ptch(+/-) allograft model of medulloblastoma and tumor growth inhibition at doses up to 92 mg/kg. GDC-0449 inhibits Gli1 with an IC50 of 0.165 μM in the medulloblastoma model and 0.267 μM in the D5123 model, according to analysis of Hh pathway activity and PK/PD modeling. Through the use of an integrated PK/PD model, pathway modulation is connected to efficacy. This relationship is steep, with more than 50% of GDC-0449's activity being linked to more than 80% of the Hh pathway's repression.[4]
Enzyme Assay
Vismodegib (GDC-0449) is an oral active inhibitor of the hedgehog pathway with an IC50 of 3 nM. Additionally, it has IC50 values of 3.0 μM and 1.4 μM for P-gp and ABCG2 inhibition, respectively.
Cell Assay
MDCKII cells are allowed to adhere after being seeded at a density of 3 × 105 cells per well into 24-well plates. After that, the medium is switched to one that contains different medications (50 μM VP, 50 μM indomethacin, or 20 μM GDC-0449 in DMSO or DMSO alone as control). Nonfluorescent calcein-AM is then added to the mixture at a final concentration of 1.0 μM and the mixture is incubated for two hours at 37 °C. Following two washes with Hank's balanced salt solution buffer containing Ca2+ and Mg2+, cells are lysed by shaking in 0.01% Triton X-100 in PBS buffer for either an hour at room temperature or an overnight at 4 °C. Using a SpectraMax M5 Multi-Detection Reader and an excitation wavelength of 495 nm and an emission wavelength of 515 nm, the lysate is then transferred into 96-well plates, and the fluorescence signal resulting from the cell-derived calcein is quantify using spectrophotometry. There is complete darkness during all manipulations. Standardized to the control, all readings are reported as mean SEM.
Animal Protocol
Mice bearing tumors are grouped into cohorts based on tumor volume when the tumors grow to a size of 200–350 mm3. A Ptch+/−, p53−/− medulloblastoma allograft is periodically dosed suboptimally to generate the vismodegib-resistant allograft, sg274. Vismodegib is taken orally as a suspension made of 0.2% tween-80 (MCT) and 0.5% methylcellulose. Digital calipers are used to calculate tumor volumes using the formula (L×W×W)/2. The percentage of the area under the fitted curve (AUC) for each dose group relative to the vehicle is used to calculate tumor growth inhibition (%TGI), which is expressed as follows: %TGI=100×1-(AUCtreatment/day)/(AUCvehicle/day).
References

[1]. Trends Pharmacol Sci . 2009 Jun;30(6):303-12.

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

[1]. Anticancer Res . 2012 Jan;32(1):89-94.

[1]. Clin Cancer Res . 2011 Jul 15;17(14):4682-92.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C19H14CL2N2O3S
Molecular Weight
421.3
Exact Mass
420.01
Elemental Analysis
C, 54.17; H, 3.35; Cl, 16.83; N, 6.65; O, 11.39; S, 7.61
CAS #
879085-55-9
Appearance
White solid powder
SMILES
CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl
InChi Key
BPQMGSKTAYIVFO-UHFFFAOYSA-N
InChi Code
InChI=1S/C19H14Cl2N2O3S/c1-27(25,26)13-6-7-14(17(21)11-13)19(24)23-12-5-8-16(20)15(10-12)18-4-2-3-9-22-18/h2-11H,1H3,(H,23,24)
Chemical Name
2-chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
Synonyms
RG3616; GDC0449; RG 3616; GDC 0449; RG-3616; GDC-0449; trade name: Erivedge
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 50~84 mg/mL (118.7~199.4 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 10mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.3736 mL 11.8680 mL 23.7361 mL
5 mM 0.4747 mL 2.3736 mL 4.7472 mL
10 mM 0.2374 mL 1.1868 mL 2.3736 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT05538091 Recruiting Drug: Vismodegib
Drug: Atezolizumab
PARP Inhibitor
Hedgehog Inhibitor
Ronald Buckanovich May 15, 2023 Phase 2
NCT00878163 Active
Recruiting
Drug: Erlotinib Hydrochloride
Drug: Vismodegib
Adult Solid Neoplasm
Recurrent Pancreatic Carcinoma
National Cancer Institute
(NCI)
March 31, 2009 Phase 1
NCT02523014 Recruiting Drug: Vismodegib
Drug: Capivasertib
Intracranial Meningioma
NF2 Gene Mutation
Alliance for Clinical Trials
in Oncology
August 2015 Phase 2
NCT01267955 Active
Recruiting
Other: Pharmacogenomic Study
Drug: Vismodegib
Metastatic Chondrosarcoma
Clear Cell Chondrosarcoma
National Cancer Institute
(NCI)
December 21, 2010 Phase 2
NCT05561634 Not yet recruiting Drug: Vismodegib
Other: Observation
Basal Cell Carcinoma
Radiotherapy; Complications
University Hospital, Lille July 2023 Phase 2
Biological Data
  • In vivo efficacy of vismodegib. Vismodegib causes tumor regression in Ptch+/− allograft medulloblastoma tumors. Clin Cancer Res . 2011 Jul 15;17(14):4682-92.
  • Hedgehog pathway modulation in Ptch+/− medulloblastoma allograft tumors following a single dose of vismodegib (A). Clin Cancer Res . 2011 Jul 15;17(14):4682-92.
  • HCC (A) and H1339 (B) cells were exposed to 25 μM GDC-0449, 50 μM GDC-0449 or 1 μM cisplatin and the cell number was assessed. Anticancer Res . 2012 Jan;32(1):89-94.
  • HCC (A) and H1339 (B) cells were exposed to 50 μM GDC-0449 or 1 μM cisplatin and the [Ca2+]cyto was measured using fluorescence microscopy. Anticancer Res . 2012 Jan;32(1):89-94.
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