Zibotentan (ZD4054)

Catalog No.S1456

Zibotentan (ZD4054) is a specific Endothelin (ET)A antagonist with IC50 of 21 nM, exhibiting no activity at ETB. Phase 3.

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Zibotentan (ZD4054) Chemical Structure

Zibotentan (ZD4054) Chemical Structure
Molecular Weight: 424.43

Validation & Quality Control

Quality Control & MSDS

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Product Information

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  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description Zibotentan (ZD4054) is a specific Endothelin (ET)A antagonist with IC50 of 21 nM, exhibiting no activity at ETB. Phase 3.
Targets Endothelin A (ETA)
IC50 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 μM. [1] Zibotentan treatment at 1 μM 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 μM) inhibits ET-1 induced EGFR transactivation in HEY and OVCA 433 cells. Zibotentan (1 μM) 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]

Protocol(Only for Reference)

Kinase Assay: [1]

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 μM 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.

Cell Assay: [3]

Cell lines HEY and OVCA 433
Concentrations Dissolved in DMSO, final concentrations 1 μM
Incubation Time 48 hours
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.

Animal Study: [3]

Animal Models Female athymic (nu+/nu+) mice bearing established HEY human ovarian carcinoma xenografts
Dosages 10 mg/kg/day
Administration Treated i.p.
Solubility 1% DMSO/30% polyethylene glycol/1% Tween 80, 30 mg/mL


Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
Start Date Phases
NCT00997945 Completed Advanced Solid Malignancies AstraZeneca 2009-10 Phase 1
NCT01000948 Enrolling by invitation Prostate Cancer|Metastasis Aarhus University Hospital|Copenhagen University Hospital 2009-10 Phase 2
NCT01119118 Terminated Prostate Cancer University of Wisconsin, Madison|AstraZeneca 2010-04 Phase 2
NCT01205711 Recruiting Colorectal Cancer National Cancer Institute (NCI)|Wales Cancer Trials Unit 2010-04 Phase 2
NCT01134497 Not yet recruiting Metastatic Breast Cancer Cardiff University 2010-09 Phase 2

Chemical Information

Download Zibotentan (ZD4054) SDF
Molecular Weight (MW) 424.43


CAS No. 186497-07-4
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Syonnyms N/A
Solubility (25°C) * In vitro DMSO 24 mg/mL (56 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 1% DMSO/30% polyethylene glycol/1% Tween 80, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name

Preparing Stock Solutions

Stock Solution (1ml DMSO) 1mM 10mM 20mM 30mM
Mass(mg) 0.42443 4.2443 8.4886 12.7329

Research Area

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