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Vandetanib trifluoroacetate (formerly also known as ZD6474) is a novel, highly potent, orally bioavailable, selective inhibitor of VEGFR2 with IC50 of 40 nM in a cell-free assay. Vandetanib selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor 2 (VEGF2), thereby blocking VEGF-stimulated endothelial cell proliferation and migration and reducing tumor vessel permeability. The inhibition of VEGFR-2 was 2.7-fold more potent than that of VEGFR-3 (Flt-4) kinase and 40-fold more potent than that of VEGFR-1. In human umbilical vein endothelial cells, treatment of ZD6474 resulted in significant inhibition of cell proliferation stimulated by VEGF and EGF with IC50 values of 60 and 170 nM, respectively.
| ln Vitro |
Vandetanib inhibits VEGFR3 and EGFR with IC50 of 110 nM and 500 nM, respectively. Vandetanib exhibits little action against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt, and IGF-1R, with an IC50 above 10 μM. In contrast, it is insensitive to PDGFRβ, Flt1, Tie-2, and FGFR1. Vandetanib has little effect on basal endothelial cell growth but inhibits HUVEC proliferation induced by VEGF, EGF, and bFGF with IC50 values of 60 nM, 170 nM, and 800 nM, respectively. With an IC50 ranging from 2.7 μM (A549) to 13.5 μM (Calu-6) [1], vandetanib inhibits the development of tumor cells. When compared to the Cat S inhibitor LHVS (IC50=0.001 μM) and tested in mouse B cell lines (IC50=1.5±0.4 μM), odanacatib is a mild antigen presentation inhibitor. With lowest inhibitory doses of 1-10 μM and 0.01 μM, respectively, Odanacatib also demonstrated lesser inhibitory effects on the processing of MHC II invariant chain protein Iip10 in mouse splenocytes as compared to LHVS [2]. Vandetanib suppresses the phosphorylation of EGFR in liver cancer cells and VEGFR-2 in HUVEC, as well as cell division [4].
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| ln Vivo |
In the H1650 xenograft model, vandetanib (15 mg/kg, po) reduces tumor growth with an IC50 of 3.5±1.2 μM, which is better than gefitinib's anti-tumor efficacy [3]. Vandetanib (50 or 75 mg/kg) reduced the number of intrahepatic metastases, upregulated VEGF, TGF-α, and EGF in tumor tissues, increased tumor cell apoptosis, inhibited tumor growth, and enhanced survival rate in tumor-bearing mice [4]. It also inhibited the phosphorylation of VEGFR-2 and EGFR in tumor tissues.
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| References |
[1]. Wedge SR, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2002 Aug 15;62(16):4645-55.
[2]. Hegedus C, et al. 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]. Takeda H, et al. Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency. Exp Cell Res. 2013 Feb 15;319(4):417-23. [4]. Inoue K, et al. 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 |
| Molecular Formula |
C22H24N4O2FBR.C2HO2F3
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|---|---|
| Molecular Weight |
589.3773
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| CAS # |
338992-53-3
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| Related CAS # |
Vandetanib;443913-73-3;Vandetanib hydrochloride;524722-52-9;Vandetanib-d6;1174683-49-8
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| SMILES |
FC1=CC(Br)=CC=C1NC2=NC=NC3=CC(OCC4CCN(CC4)C)=C(C=C23)OC.O=C(O)C(F)(F)F
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| 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)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6967 mL | 8.4835 mL | 16.9670 mL | |
| 5 mM | 0.3393 mL | 1.6967 mL | 3.3934 mL | |
| 10 mM | 0.1697 mL | 0.8483 mL | 1.6967 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.
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