Vandetanib (ZD-6474)

Alias: ZD 6474; AZD-6474; ZD6474; AZD6474; CHEBI:38942; Vandetanib; ZD-6474; AZD 6474; Zactim; Caprelsa
Cat No.:V0494 Purity: ≥98%
Vandetanib (formerly also known as ZD6474; trade name Caprelsa) is a highly potent, orally bioavailable, and selective inhibitor of VEGFR2 with potential anticancer activity.
Vandetanib (ZD-6474) Chemical Structure CAS No.: 443913-73-3
Product category: VEGFR
This product is for research use only, not for human use. We do not sell to patients.
Size Price Stock Qty
10mg
25mg
50mg
100mg
250mg
500mg
1g
Other Sizes

Other Forms of Vandetanib (ZD-6474):

  • Vandetanib trifluoroacetate (ZD-6474)
  • Vandetanib hydrochloride (ZD-6474)
  • Vandetanib-d6 (ZD6474-d6)
  • Vandetanib-d4 (vandetanib d4)
Official Supplier of:
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Vandetanib (formerly also known as ZD6474; trade name Caprelsa) is a highly potent, orally bioavailable, and selective inhibitor of VEGFR2 with potential anticancer activity. In a test without cells, it inhibits VEGFR2 with an IC50 of 40 nM. In April 2011, the FDA approved vandetanib for the treatment of advanced thyroid cancer. Vandetanib reduces tumor vessel permeability by specifically inhibiting the tyrosine kinase activity of vascular endothelial growth factor receptor 2 (VEGF2). This prevents VEGF-stimulated endothelial cell migration and proliferation.

Biological Activity I Assay Protocols (From Reference)
Targets
VEGFR2 (IC50 = 40 nM); VEGFR3 (IC50 = 110 nM); EGFR/HER1 (IC50 = 500 nM)
ln Vitro

Vandetanib suppresses EGFR and VEGFR3 with IC50 values of 500 nM and 110 nM, respectively. Vandetanib almost completely lacks activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt, and IGF-1R, with an IC50 above 10 μM. It is insensitive to PDGFRβ, Flt1, Tie-2, and FGFR1. Vandetanib has no effect on basal endothelial cell growth but inhibits the proliferation of HUVECs stimulated by VEGF, EGF, and bFGF at IC50 values of 60 nM, 170 nM, and 800 nM. With an IC50 range of 2.7 μM (A549) to 13.5 μM (Calu-6)[1], vandetanib inhibits the growth of tumor cells. In a mouse B cell line, odanacatib's antigen presentation inhibitory activity was found to be weak (IC50=1.5±0.4 μM) in contrast to the Cat S inhibitor LHVS (IC50=0.001 μM) in the same assay. Additionally, odanacatib exhibits a weaker inhibitory effect on the MHC II invariant chain protein Iip10 processing in mouse splenocytes when compared to LHVS (minimum inhibitory concentrations of 1–10 μM versus 0.01 μM, respectively)[2]. Vandetanib prevents cell growth by suppressing the phosphorylation of EGFR in hepatoma cells and VEGFR-2 in HUVECs[4].

ln Vivo
Vandetanib (15 mg/kg, p.o.) inhibits tumor growth with an IC50 of 3.5±1.2 μM, showing a superior anti-tumor effect over gefitinib in the H1650 xenograft model[3]. Vandetanib (50 or 75 mg/kg) significantly lowers tumor vessel density, increases tumor cell apoptosis, suppresses tumor growth, increases survival, decreases the number of intrahepatic metastases, and upregulates VEGF, TGF-α, and EGF in tumor tissues in tumor-bearing mice[4]. It also suppresses the phosphorylation of VEGFR-2 and EGFR in tumor tissues.
Enzyme Assay
In 96-well plates coated with a poly(Glu, Ala, Tyr) 6:3:1 random copolymer substrate, vandetanib is incubated with the enzyme, 10 mM MnCl2, and 2 μM ATP. The next step is to identify phosphorylated tyrosine by sequentially incubating 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid), a horseradish peroxidase-linked sheep antimouse immunoglobulin antibody, and a mouse IgG anti-phosphotyrosine 4G10 antibody. To investigate selectivity against tyrosine kinases linked to FGFR1, c-kit, erbB2, IGF-1R, FAK, PDGFRβ, Tie-2, and FGFR1, this methodology is modified. Appropriate ATP concentrations at or slightly below the corresponding Km (0.2–14 μM) were used in all enzyme assays (tyrosine or serine–threonine). Selectivity against serine-threonine kinases (CDK2, AKT, and PDK1) is investigated in 96-well plates using a pertinent scintillation proximity-assay (SPA). The conditions for the CDK2 assays were as follows: 10 mM MnCl2, 4.5 μM ATP, 0.15 μCi of [γ-33 P]ATP/reaction, 50 mM HEPES (pH 7.5), 1 mM DTT, 0.1 mM sodium orthovanadate, 0.1 mM sodium fluoride, 10 mM sodium glycerophosphate, 1 mg/mL BSA fraction V, and a retinoblastoma substrate (a portion of the retinoblastoma gene, 792–928, expressed in a glutathione S-transferase expression system; 0.22 μM initial concentration). The reactions are conducted at room temperature for 60 minutes and then quenched for two hours using 150 μL of a solution that contains 0.8 mg/reaction of protein A SPA-polyvinyltoluene beads, 3 μg of rabbit immunoglobulin anti-glutathione S-transferase antibody, and EDTA (62 mM final concentration). After that, the plates are sealed, centrifuged for five minutes at 1200 x g, and counted for thirty seconds using a Microplate scintillation counter.
Cell Assay
The MTT assay is modified to measure growth inhibition. In a nutshell, the cells are exposed to either vandetanib or gefitinib for 72 hours after being plated at a density of 2000 cells per well in 96-well plates. Triples of each assay are run. For every medication, the 50% inhibitory concentration (IC50) is calculated using the mean±standard deviation (SD).
Animal Protocol
Each mouse has one million subcutaneous injections of H1650 cells, or H1650/PTEN cells (H1650 cells with a transfected PTEN gene), in its back. Mice are randomly assigned to three groups on the tenth day following injection, and they are given either vehicle, vandetanib (15 mg/kg/day), or gefitinib (15 mg/kg/day). Five times a week, once daily p.o. administrations of vehicle, vandetanib, and gefitinib are given. Body weight and tumor volume (width × width × length/2) are measured on a regular basis. The expression for tumor volumes is mean±SD. Tumor volume differences are assessed using the Student's t-test.
References

[1]. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2002 Aug 15;62(16):4645-55.

[2]. Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: implications for the emergence and reversal of cancer drug resistance. Biochem Pharmacol. 2012 Aug 1;84(3):260-7.

[3]. Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency. Exp Cell Res. 2013 Feb 15;319(4):417-23.

[4]. Vandetanib, an inhibitor of VEGF receptor-2 and EGF receptor, suppresses tumor development and improves prognosis of liver cancer in mice. Clin Cancer Res. 2012 Jul 15;18(14):3924-33.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C22H24BRFN4O2
Molecular Weight
475.35
Exact Mass
474.11
Elemental Analysis
C, 55.59; H, 5.09; Br, 16.81; F, 4.00; N, 11.79; O, 6.73
CAS #
443913-73-3
Appearance
Light yellow to yellow solid powder
SMILES
CN1CCC(CC1)COC2=C(C=C3C(=C2)N=CN=C3NC4=C(C=C(C=C4)Br)F)OC
InChi Key
UHTHHESEBZOYNR-UHFFFAOYSA-N
InChi Code
InChI=1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27)
Chemical Name
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine
Synonyms
ZD 6474; AZD-6474; ZD6474; AZD6474; CHEBI:38942; Vandetanib; ZD-6474; AZD 6474; Zactim; Caprelsa
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: ~4 mg/mL (~8.4 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
1% CMC Na: 30mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.1037 mL 10.5186 mL 21.0371 mL
5 mM 0.4207 mL 2.1037 mL 4.2074 mL
10 mM 0.2104 mL 1.0519 mL 2.1037 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
NCT01496313 Active
Recruiting
Drug: 300mg vandetanib
Drug: 150mg vandetanib
Thyroid Cancer Genzyme, a Sanofi Company/td> August 28, 2012 Phase 4
NCT01582191 Active
Recruiting
Drug: Vandetanib
Drug: Everolimus
Advanced Malignant Neoplasm
Metastatic Malignant Neoplasm
M.D. Anderson Cancer Center May 14, 2012 Phase 1
NCT00537095 Active
Recruiting
Drug: Vandetanib
Other: Placebo
Thyroid Neoplasms Genzyme, a Sanofi Company September 29, 2007 Phase 2
NCT04211337 Active
Recruiting
Drug: Selpercatinib
Drug: Vandetanib
Medullary Thyroid Cancer Loxo Oncology, Inc. February 11, 2020 Phase 3
NCT00410761 Active
Recruiting
Drug: ZD6474
(Vandetanib)
Thyroid Cancer Genzyme, a Sanofi Company November 30, 2006 Phase 3
Biological Data
  • Inhibitory effects of vandetanib on cell proliferation, and phosphorylation of VEGFR-2 and EGFR. Clin Cancer Res . 2012 Jul 15;18(14):3924-33.
  • Serial changes in tumor growth induced by treatment with vandetanib in mice carrying subcutaneously implanted human hepatoma cell tumors. Clin Cancer Res . 2012 Jul 15;18(14):3924-33.
  • Vandetanib inhibits tumor growth in the liver in nude mice. Clin Cancer Res . 2012 Jul 15;18(14):3924-33.
  • Beneficial effects of vandetanib on the survival time and the intrahepatic metastasis in mice implanted with KYN-2 cells. Clin Cancer Res . 2012 Jul 15;18(14):3924-33.
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