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Zibotentan (ZD4054)

Zibotentan (ZD4054)

Item no.	S1456-50
Manufacturer	Selleckchem
CASRN	186497-07-4
Amount	50 mg
Category	Oncology Neuroscience Neural Signaling Inhibitors & Compound Libraries Small Molecules By Organ Lung Cancer Skin Cancer Bladder Cancer Colorectal Cancer Testicular & Prostate Cancer Uterine, Ovarian & Cervical Cancer
Type	Inhibitors
Specific against	other
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	Endothelin A (ETA);ETA Receptor
Similar products	Zibotentan
Available
Administration	Treated i.p.
Animal Models	Female athymic (nu+/nu+) mice bearing established HEY human ovarian carcinoma xenografts
Cell lines	HEY and OVCA 433
Clinical Trials	A Phase III study of Zibotentan in patients with hormone resistant prostate cancer (HRPC) and bone metastases has been completed.
Concentrations	Dissolved in DMSO, final concentrations 1 uM
Description	Zibotentan (ZD4054) is a specific Endothelin A (ETA) antagonist with IC50 of 21 nM.
Dosages	10 mg/kg/day
Formulation	Dissolved in DMSO, and diluted in PBS
IC50	21 nM [1], 21 nM [1], 21 nM [1], 21 nM [1], 21 nM [1], 21 nM [1]
In vitro	As Zibotentan specifically inhibits ETA-mediated antiapoptotic effects, but not ETB-mediated proapoptotic effects in human and rat smooth muscle cells, Zibotentan binds to endothelin A receptor (ETA) with high affinity with Ki of 13 nM, and has no affinity for endothelin B receptor (ETB) with IC50 of >10 uM. [1] Zibotentan treatment at 1 uM inhibits ET-1 induced mitogenic activity in ovarian carcinoma cell lines HEY and OVCA 433 secreting ET-1 and expressing ETA and ETB mRNA. [2] ZD4054 (1 uM) inhibits ET-1 induced EGFR transactivation in HEY and OVCA 433 cells. Zibotentan (1 uM) reverts ET-1 mediated epithelial-mesenchymal transition (EMT), by enhancing E-cadherin expression and promoter activity, and inhibiting vascular endothelial growth factor (VEGF) secretion and invasiveness in HEY and OVCA 433 cells. [3] Zibotentan also potently inhibits the basal and ET-1 induced cell proliferation in SKOV-3 and A-2780 cells, associated with the inhibition of AKT and p42/44MAPK phosphorylation, and with increased apoptosis through the inhibition of bcl-2 and activation of caspase-3 and poly(ADP-ribose) polymerase proteins. [4]
In vivo	Administration of Zibotentan at 10 mg/kg/day for 21 days potently inhibits the growth of HEY ovarian carcinoma xenografts in mice by 69% with no associated toxicity, which is in association with the blocking of cell proliferation evaluated by 37% inhibition of the Ki-67 expression, and the 62% inhibition of tumor-induced vascularization. Consistently, Zibotentan treatment significantly inhibits the expression of matrix metalloproteinase-2 (MMP-2) and VEGF, as well as the activation of p42/44 MAPK and EGFR, and potently enhances the expression of E-cadherin. [3]
Incubation Time	48 hours
Kinase Assay	Receptor-binding assays, The inhibition by Zibotentan (varying concentrations) of 125iodine-ET-1 binding to cloned human ETA is assessed using standard radioligand-binding techniques. Human recombinant ETA is expressed in mouse erythroleukaemic cells, and cell membranes prepared for competitive binding studies using 125iodine-ET-1 as the radioligand. Incubations are carried out in triplicate in the presence of Zibotentan, 100 pM to 100 uM in half-log increments, and inhibition of ET-1 binding is expressed as the geometric mean pIC50 value (concentration to inhibit 50% of binding) with a 95% confidence interval (CI). The affinity of Zibotentan for cloned human ETA is also assessed using the equation of Cheng and Prusoff to determine the equilibrium dissociation constant (Ki) in a further receptor-binding screen utilizing a greater number of concentration-response curves determined in three separate studies.
Method	Cells are serum starved by incubation for 24 hours in serum-free DMEM before exposed to Zibotentan for 48 hours. After the treatment, cells are lysed and the supernatant is recovered and assayed for histone-associated DNA fragments, at 405 nm by the use of a microplate reader. For detection of early apoptotic events, floating and adherent cells are collected. Cells are double stained with FITC-conjugated Annexin V and propidium iodide using the Vybrant Apoptosis Kit and are immediately analyzed by cytofluorometric analysis.
Molecular Weight (MW)	424, 43
Picture ChemicalStructure Description	Zibotentan (ZD4054) Chemical Structure
Solubility (25C)	DMSO 24 mg/mL, Water <1 <1 mg/mL, Ethanol <1 mg/mL
Storage	2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO

Note: The presented information and documents (Manual, Product Datasheet, Safety Datasheet and Certificate of Analysis) correspond to our latest update and should serve for orientational purpose only. We do not guarantee the topicality. We would kindly ask you to make a request for specific requirements, if necessary.

All products are intended for research use only (RUO). Not for human, veterinary or therapeutic use.

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Amount: 50 mg

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