Vandetanib

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Chemical Structure| 443913-73-3 同义名 : 凡德他尼(ZD6474) ;ZD6474;CH 331;Zactima
CAS号 : 443913-73-3
货号 : A126372
分子式 : C22H24BrFN4O2
纯度 : 99%
分子量 : 475.354
MDL号 : MFCD07772346
存储条件：

Pure form Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 20 mg/mL(42.07 mM)，配合低频超声，并水浴加热至45℃助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+40% PEG300+water 1.3 mg/mL clear

PO 0.5% CMC-Na 30 mg/mL suspension

生物活性
靶点

  • EGFR/ErbB1

    EGFR, IC50:500 nM

  • VEGFR3

    VEGFR3, IC50:110 nM

  • VEGFR2

    VEGFR2, IC50:40 nM
描述 VEGF/VEGFR (vascular endothelial growth factor vascular endothelial growth factor receptor) pathway plays a key role in tumor angiogenesis by promotion of vascular and lymphatic endothelial, as well as survival, and invasion, thus resulting in neovascularization, tumor growth and metastasis. Vandetanib is a selective VEGFR2 inhibitor with IC50 value of 40nM versus IC50 of 110nM/1600nM for VEGFR3/VEGFR1, also show inhibitory potency to EGFR, PDGFRβ, Tie-2 and FGFR1 with IC50 values of 0.5μM, 1.1μM, 2.5μM and 3.6μM, respectively, in kinase activity assays. Consistent with the selectivity for inhibition of the different RTKs, Vandetanib showed most potency to VEGF-stimulated HUVEC proliferation with IC50 value of 60nM, versus IC50 values of 170 and 800nM for EGF- and bFGF-stimulated cell growth, respectively[1]. The inactivation by Vandetanib on kinase activity of its targets was confirmed by the cellular studies as exposure to Vandetanib at concentration of 1, 5 and 10μM caused inhibition of VEGF-induced p-VEGFR2 in HUVECs, as well as suppressed EGF-induced p-EGFR in the hepatoma cell lines[2]. Vandetanib showed anti-proliferative effect on A549 tumor cells at concentration ranging in 2.7±0.5μM and Calu-6 tumor cells at concentration ranging in 13.5±1.5μM, 45- and 225-fold more than those to inhibit VEGF-stimulated HUVEC proliferation. As prediction of its effect on VEGFR, the significant anti-angiogenesis by Vandetanib can be observed in mice intradermally implanted A549 tumor cells with reduction of tumor-induced blood vessel formation by 63%/79% at dose of 50/100mg/kg/day, orally, for 5 days. Oral administration of Vandetanib once daily produced anti-tumor effect in a dose-dependent manner in all tested models from different origins, including Calu-6 (lung), PC-3 (prostate), MDA-MB-231 (breast), SKOV-3 (ovary), SW620 (colon), A549 (lung), A431 (vulva), B16-F10(AP3) (murine melanoma) and Lewis Lung (murine lung) xenografts, at dose of 12.5, 25, 50 and 100mg/kg[1].
作用机制 Vandetanib is an ATP-competitive inhibitor of VEGFR, EGFR and RET kinases.[3]
细胞研究
细胞系 浓度 检测类型 检测时间 活性说明 数据源
201T 2.5 μM Function Assay 48 h inhibits phospho-MAPK following EGF 22258476
201T 1/5/10 μM Function Assay 48 h blocks the phosphorylation of Akt induced by VEGFC 22258476
211H Growth Inhibition Assay 72 h IC50=2.2 μM 18364248
临床研究
NCT号 适应症或疾病 临床期 招募状态 预计完成时间 地点
NCT02142036 Metastatic Cancer Phase 2 Active, not recruiting January 2022 Norway ... 展开 >> Akershus University Hospital Lillestrøm, Norway, 1478 The Norwegian Radium Hospital Oslo, Norway, 0379 收起 <<
NCT03413176 - Completed - France ... 展开 >> AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology, CIC-1421, Pharmacovigilance Unit, INSERM. Paris, France, 75013 收起 <<
NCT02788201 Urothelial Carcinoma ... 展开 >> Bladder Cancer Urinary Bladder Neoplasms 收起 << Phase 2 Recruiting July 1, 2020 United States, Maryland ... 展开 >> National Institutes of Health Clinical Center Recruiting Bethesda, Maryland, United States, 20892 Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937 收起 <<
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.10mL

0.42mL

0.21mL

10.52mL

2.10mL

1.05mL

21.04mL

4.21mL

2.10mL
参考文献

[1]Vitagliano D, De Falco V, et al. The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells. Endocr Relat Cancer. 2010 Nov 30;18(1):1-11.

[2]Wedge SR, Ogilvie DJ, 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.

[3]Inoue K, Torimura T, 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.

[4]Yoshikawa D, Ojima H, et al. Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma. Br J Cancer. 2009;100(8):1257-66.

[5]Attwa MW, Kadi AA, et al. Identification and characterization of in vivo, in vitro and reactive metabolites of vandetanib using LC-ESI-MS/MS. Chem Cent J. 2018 Sep 24;12(1):99.

[6]Pozo K, Zahler S, et al. Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer. Oncotarget. 2018 Dec 28;9(102):37662-37675.

[7]ZD6474