Zibotentan (ZD4054)

For research use only.

Catalog No.S1456

2 publications

Zibotentan (ZD4054) Chemical Structure

CAS No. 186497-07-4

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

Selleck's Zibotentan (ZD4054) has been cited by 2 publications

1 Customer Review

  • (E and F) Photomicrograph and quantifications showing reducing in inflammation in steatosis in IL27RA-/-p53H/1 mice treated with ZD4054 (N=9), when compared to sham treated mice (N=7). Chi-square test was used to determine the differences among these two groups. In vivo data with ZD4054 inhibitor was repeated twice with similar results. (i) WT, (ii) IL27RA-/-, (iii) p53H/1, or (iv) IL27RA-/-p53H/1. Dots indicate data from liver of individual mice. Pictures taken at 2003. *P < 0.05. Abbreviation: DAPI, 40,6-diamidino-2-phenylindole.

    Hepatology, 2016, 63(3):1000-12. . Zibotentan (ZD4054) purchased from Selleck.

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Choose Selective Endothelin Receptor Inhibitors

Biological Activity

Description Zibotentan (ZD4054) is a specific Endothelin (ET)A antagonist with IC50 of 21 nM, exhibiting no activity at ETB. Phase 3.
ET-A [1]
21 nM
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]


Kinase Assay:[1]
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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 Research:[3]
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  • 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.
    (Only for Reference)
Animal Research:[3]
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  • Animal Models: Female athymic (nu+/nu+) mice bearing established HEY human ovarian carcinoma xenografts
  • Dosages: 10 mg/kg/day
  • Administration: Treated i.p.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 24 mg/mL (56.54 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
1% DMSO+30% polyethylene glycol+1% Tween 80
For best results, use promptly after mixing.
30 mg/mL

* 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 Information

Molecular Weight 424.43


CAS No. 186497-07-4
Storage powder
in solvent
Synonyms N/A
Smiles CC1=CN=C(C(=N1)OC)NS(=O)(=O)C2=C(N=CC=C2)C3=CC=C(C=C3)C4=NN=CO4

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% DMSO % % Tween 80 % ddH2O

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04724837 Recruiting Drug: Zibotentan|Drug: Dapagliflozin|Drug: Placebo Chronic Kidney Disease AstraZeneca April 28 2021 Phase 2
NCT01119118 Terminated Drug: ZD4054 Prostate Cancer University of Wisconsin Madison|AstraZeneca April 2010 Phase 2
NCT01000948 Terminated Drug: ZD4054 Prostate Cancer|Metastasis Aarhus University Hospital|Rigshospitalet Denmark October 2009 Phase 2
NCT00997945 Completed Drug: ZD4054 (Zibotentan) Advanced Solid Malignancies AstraZeneca October 2009 Phase 1
NCT00713791 Completed Drug: ZD4054 Healthy AstraZeneca June 2008 Phase 1

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Endothelin Receptor Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID