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50mg |
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250mg |
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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. 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.
Targets |
hedgehog ( IC50 = 3 nM ); P-gp ( IC50 = 3.0 μM ); ABCG2 ( IC50 = 1.4 μM )
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ln Vitro |
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ln Vivo |
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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.
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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.
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Animal Protocol |
Mice:
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). Rats: Vismodegib (10 mg/kg) drug was gavaged orally for 14 days in rats to significantly decrease the SHH signaling proteins [SHH, protein patched homolog 1 (PTCH1), smoothened protein (SMO), glioma-associated oncogene homolog 1 (GLI1)], induce damage in SMG tissue, and affect salivary functional markers AQP5 and Keratin5. After that, in conjunction with vismodegib administration, PBM was performed using an 850 nm high-power light-emitting diode (LED) device treated daily for 6 days at varying total energy densities of 60, 120, and 180 J/cm2 in at least 3 rats per group. The test results were confirmed by Western blot, immunofluorescence staining, and hematoxylin and eosin staining, and the statistics were t-test or one-way analysis of variance (ANOVA) with Tukey's multiple comparisons tests.[5] Preclinical PK studies used in our study were previously reported (Wong et al., 2009). For the intravenous PK studies in rats, dogs, and monkeys, three male animals of each species were given a single intravenous dose of 1 mg/kg vismodegib in 30%, 80%, and 80% polyethylene glycol (PEG 400), respectively. For oral PK, three male animals for each species were given an oral vismodegib dose at 5 mg/kg (rats) or 2 mg/kg (dogs and monkeys) formulated in 0.5% methylcellulose with 0.2% Tween 80. For all studies, sequential plasma samples were collected following drug administration and vismodegib plasma concentrations were determined by liquid chromatography tandem mass spectrometry (LC/MS/MS)[6]. Based on the results of in vitro and in vivo studies, vismodegib is not mutagenic. No evidence of carcinogenicity was found in mice and rats given vismodegib. A 26-week rat fertility study found that at doses of 100 mg/kg/day, vismodegib has no effects on male reproductive organs or fertility. In female rats, the administration of vismodegib was associated with decreased implantations, increased percent preimplantation loss, and decreased numbers of dams with viable embryos [7]. |
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References |
Molecular Formula |
C19H14CL2N2O3S
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Molecular Weight |
421.3
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Exact Mass |
420.01
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Elemental Analysis |
C, 54.17; H, 3.35; Cl, 16.83; N, 6.65; O, 11.39; S, 7.61
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CAS # |
879085-55-9
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Related CAS # |
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Appearance |
Off-white to light yellow solid powder
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LogP |
2.98
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tPSA |
84.51
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SMILES |
CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl
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InChi Key |
BPQMGSKTAYIVFO-UHFFFAOYSA-N
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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)
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Chemical Name |
2-chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
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Synonyms |
RG3616; GDC0449; RG 3616; GDC 0449; RG-3616; GDC-0449; trade name: Erivedge
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (5.93 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 10mg/mL |
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.
Calculation results
Working concentration: mg/mL;
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.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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 |
In vivo efficacy of vismodegib. Vismodegib causes tumor regression in Ptch+/− allograft medulloblastoma tumors. Clin Cancer Res . 2011 Jul 15;17(14):4682-92. td> |
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. td> |
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. td> |
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. td> |