Vandetanib
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MedKoo CAT#: 558308

CAS#: 443913-73-3 (free base)

Description: Vandetanib is an orally bioavailable 4-anilinoquinazoline. 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. This agent also blocks the tyrosine kinase activity of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that mediates tumor cell proliferation and migration and angiogenesis. Vandetanib was the first drug to be approved by FDA (April 2011) for treatment of late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery. Vandetanib was approved in 2011.


Chemical Structure

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Vandetanib
CAS# 443913-73-3 (free base)

Theoretical Analysis

MedKoo Cat#: 558308
Name: Vandetanib
CAS#: 443913-73-3 (free base)
Chemical Formula: C22H24BrFN4O2
Exact Mass: 474.10667
Molecular Weight: 475.35
Elemental Analysis: C, 55.59; H, 5.09; Br, 16.81; F, 4.00; N, 11.79; O, 6.73

Price and Availability

Size Price Availability Quantity
50.0mg USD 65.0 Ready to ship
100.0mg USD 90.0 Ready to ship
200.0mg USD 150.0 Ready to ship
500.0mg USD 250.0 Ready to ship
1.0g USD 450.0 Ready to ship
2.0g USD 750.0 Ready to ship
5.0g USD 1250.0 2 weeks
50.0g USD 6950.0 2 Weeks
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Related CAS #: 443913-73-3 (free base)   338992-00-0 (fumarate)    

Synonym: AZD6474; AZD 6474; AZD-6474; ZD6474; ZD 6474; ZD-6474; CHEBI:38942; Vandetanib; Zactim; Caprelsa

IUPAC/Chemical Name: N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine

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)

SMILES Code: CN1CCC(COC2=CC3=NC=NC(NC4=CC=C(Br)C=C4F)=C3C=C2OC)CC1

Appearance: Light yellow to yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Vandetanib (D6474) is an inhibitor of VEGFR2/KDR tyrosine kinase activity (IC50=40 nM).
In vitro activity: As shown in Figure 1, vandetanib can significantly reduce cell proliferation compared with control and NC groups. About 12 hours after treatment, cell viability decreased about half by MTT assay. This study hypothesized that apoptosis might be the cause of this effect. Therefore, Annexin V/PI staining was performed for three groups at 24 hours after treatment. Flow cytometry assay showed that vandetanib group produced about four folds more Annexin V/PI double positive cells compared with other two groups. Cell cycle analysis was performed. As to G2/M phage, there was significant reduction compared with control group (P<0.05). As to G0/G1 phage, the percentage was improved (P>0.05). Thus, vandetanib inhibited the proliferation of breast cancer cells through regulating G2/M phage and subsequently contributed to growth inhibition. Reference: Onco Targets Ther. 2018; 11: 8543–8553. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278704/
In vivo activity: To investigate the antitumor activity of vandetanib in tumors harboring the activating Egfr mutation, 7-week-old transgenic mice were administered vandetanib (6mg/kg) or vehicle daily for 7 days, after which they were killed. After administering vandetanib for 2 days, the area occupied by tumor cells decreased compared with the pre-administration value (Fig. 1B, C). Furthermore, tumor cell disappeared in the seeing length after the administration of vandetanib for 7 days (Fig. 1D). The expression of total EGFR and total VEGFR2 in the lungs of the transgenic mice, as assessed by immunohistochemistry, was slightly suppressed in the vandetanib-treated animals compared to the animals treated with vehicle alone, while the pEGFR and pVEGFR levels were markedly decreased in the transgenic mice treated with vandetanib relative to those treated with vehicle (Fig. 2). Reference: Acta Med Okayama. 2016 Aug;70(4):243-53. https://pubmed.ncbi.nlm.nih.gov/27549668/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 22.5 47.33
DMF 2.0 4.21
DMF:PBS (pH 7.2) (1:1) 0.5 1.05

Preparing Stock Solutions

The following data is based on the product molecular weight 475.35 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Li L, Yu J, Jiao S, Wang W, Zhang F, Sun S. Vandetanib (ZD6474) induces antiangiogenesis through mTOR-HIF-1 alpha-VEGF signaling axis in breast cancer cells. Onco Targets Ther. 2018 Nov 29;11:8543-8553. doi: 10.2147/OTT.S175578. PMID: 30555244; PMCID: PMC6278704. 2. Zhou Y, Zhang Y, Zou H, Cai N, Chen X, Xu L, Kong X, Liu P. The multi-targeted tyrosine kinase inhibitor vandetanib plays a bifunctional role in non-small cell lung cancer cells. Sci Rep. 2015 Feb 27;5:8629. doi: 10.1038/srep08629. PMID: 25720956; PMCID: PMC4342569. 3. Osawa M, Ohashi K, Kubo T, Ichihara E, Takata S, Takigawa N, Takata M, Tanimoto M, Kiura K. Effect of Vandetanib on Lung Tumorigenesis in Transgenic Mice Carrying an Activating Egfr Gene Mutation. Acta Med Okayama. 2016 Aug;70(4):243-53. doi: 10.18926/AMO/54499. PMID: 27549668. 4. Hatem R, Labiod D, Château-Joubert S, de Plater L, El Botty R, Vacher S, Bonin F, Servely JL, Dieras V, Bièche I, Marangoni E. Vandetanib as a potential new treatment for estrogen receptor-negative breast cancers. Int J Cancer. 2016 May 15;138(10):2510-21. doi: 10.1002/ijc.29974. Epub 2016 Jan 6. PMID: 26686064.
In vitro protocol: 1. Li L, Yu J, Jiao S, Wang W, Zhang F, Sun S. Vandetanib (ZD6474) induces antiangiogenesis through mTOR-HIF-1 alpha-VEGF signaling axis in breast cancer cells. Onco Targets Ther. 2018 Nov 29;11:8543-8553. doi: 10.2147/OTT.S175578. PMID: 30555244; PMCID: PMC6278704. 2. Zhou Y, Zhang Y, Zou H, Cai N, Chen X, Xu L, Kong X, Liu P. The multi-targeted tyrosine kinase inhibitor vandetanib plays a bifunctional role in non-small cell lung cancer cells. Sci Rep. 2015 Feb 27;5:8629. doi: 10.1038/srep08629. PMID: 25720956; PMCID: PMC4342569.
In vivo protocol: 1. Osawa M, Ohashi K, Kubo T, Ichihara E, Takata S, Takigawa N, Takata M, Tanimoto M, Kiura K. Effect of Vandetanib on Lung Tumorigenesis in Transgenic Mice Carrying an Activating Egfr Gene Mutation. Acta Med Okayama. 2016 Aug;70(4):243-53. doi: 10.18926/AMO/54499. PMID: 27549668. 2. Hatem R, Labiod D, Château-Joubert S, de Plater L, El Botty R, Vacher S, Bonin F, Servely JL, Dieras V, Bièche I, Marangoni E. Vandetanib as a potential new treatment for estrogen receptor-negative breast cancers. Int J Cancer. 2016 May 15;138(10):2510-21. doi: 10.1002/ijc.29974. Epub 2016 Jan 6. PMID: 26686064.

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1: Duplomb S, Benoit A, Mechtouff-Cimarelli L, Cho TH, Derbel O, Peix JL, de la Fouchardière C. Unusual Adverse Event With Vandetanib in Metastatic Medullary Thyroid Cancer. J Clin Oncol. 2011 Dec 12. [Epub ahead of print] PubMed PMID: 22162581.

2: Langmuir PB, Yver A. Vandetanib for the Treatment of Thyroid Cancer. Clin Pharmacol Ther. 2011 Dec 7. doi: 10.1038/clpt.2011.272. [Epub ahead of print] PubMed PMID: 22158569.

3: Ernesto S, Arpin D, Nesme P, Pérol M. Diffuse Interstitial Lung Disease Linked to Vandetanib. Clin Lung Cancer. 2011 Nov 29. [Epub ahead of print] PubMed PMID: 22133289.

4: Koch L. Pharmacotherapy: Vandetanib-a new therapeutic option in advanced medullary thyroid cancer. Nat Rev Endocrinol. 2011 Nov 15;8(1):1. doi: 10.1038/nrendo.2011.198. PubMed PMID: 22083086.

5: Solomon B, Rischin D. Progress in Molecular Targeted Therapy for Thyroid Cancer: Vandetanib in Medullary Thyroid Cancer. J Clin Oncol. 2011 Oct 24. [Epub ahead of print] PubMed PMID: 22025155.

6: Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ. Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial. J Clin Oncol. 2011 Nov 21. [Epub ahead of print] PubMed PMID: 22025146.

7: Qi WX, Tang LN, He AN, Shen Z, Yao Y. The role of vandetanib in the second-line treatment for advanced non-small-cell-lung cancer: a meta-analysis of four randomized controlled trials. Lung. 2011 Dec;189(6):437-43. Epub 2011 Oct 11. PubMed PMID: 21986852.

8: Ahn J, Wee WR, Lee JH, Hyon JY. Vortex keratopathy in a patient receiving vandetanib for non-small cell lung cancer. Korean J Ophthalmol. 2011 Oct;25(5):355-7. Epub 2011 Sep 20. PubMed PMID: 21976946; PubMed Central PMCID: PMC3178773.

9: Giovannetti E, Zucali PA, Assaraf YG, Leon LG, Smid K, Alecci C, Giancola F, Destro A, Gianoncelli L, Lorenzi E, Roncalli M, Santoro A, Peters GJ. Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin. Br J Cancer. 2011 Nov 8;105(10):1542-53. doi: 10.1038/bjc.2011.400. Epub 2011 Oct 4. PubMed PMID: 21970874.

10: Saletti P, Sessa C, De Dosso S, Cerny T, Renggli V, Koeberle D. Phase I dose-finding study of vandetanib in combination with gemcitabine in locally advanced unresectable or metastatic pancreatic adenocarcinoma. Oncology. 2011;81(1):50-4. Epub 2011 Sep 15. PubMed PMID: 21921646.



Additional Information

Vandetanib is being developed by AstraZeneca. In April 2011, Vandetanib became the first drug to be approved by FDA for treatment of late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery. Vandetanib was first initially marketed without a tradename, and is being marketed under the trade name Caprelsa since August 2011. (source: http://en.wikipedia.org/wiki/ Vandetanib ).
 
Vandetanib is also  a medication currently undergoing clinical trials as a potential targeted treatment for non-small-cell lung cancer. There have been some promising results from a phase III trial with docetaxel.  There have also been ambivalent results when used with pemetrexed. Another trial with docetaxel was recruiting in July 2009. AstraZeneca withdrew EU regulatory submissions for Zactima in October 2009 after trials showed no benefit when the drug was administered alongside chemotherapy. (source: http://en.wikipedia.org/wiki/ Vandetanib ).