Home GPCR & G Protein Endothelin Receptor antagonist Zibotentan (ZD4054) For research use only.

Zibotentan (ZD4054)

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

Zibotentan (ZD4054) Chemical Structure

Zibotentan (ZD4054) Chemical Structure

CAS No. 186497-07-4

Purity & Quality Control

Batch: S145601 DMSO]24 mg/mL]false]Water]Insoluble]false]Ethanol]Insoluble]false Purity: 99.15%
99.15

Zibotentan (ZD4054) Related Products

Signaling Pathway

Endothelin Receptor Signaling Pathways

Endothelin Receptor Signaling Pathway

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
ET-A [1]
21 nM
In vitro
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]
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 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 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.
In Vivo
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]
Animal Research Animal Models Female athymic (nu+/nu+) mice bearing established HEY human ovarian carcinoma xenografts
Dosages 10 mg/kg/day
Administration Treated i.p.
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01119118 Terminated
Prostate Cancer
University of Wisconsin Madison|AstraZeneca
 April 2010 Phase 2
NCT01000948 Terminated
Prostate Cancer|Metastasis
Aarhus University Hospital|Rigshospitalet Denmark
 October 2009 Phase 2
NCT00997945 Completed
Advanced Solid Malignancies
AstraZeneca
 October 2009 Phase 1
NCT00713791 Completed
Healthy
AstraZeneca
 June 2008 Phase 1

Chemical Information & Solubility

Molecular Weight 424.43 Formula

C19H16N6O4S
CAS No. 186497-07-4 SDF Download Zibotentan (ZD4054) SDF
Smiles CC1=CN=C(C(=N1)OC)NS(=O)(=O)C2=C(N=CC=C2)C3=CC=C(C=C3)C4=NN=CO4
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 24 mg/mL ( (56.54 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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In vivo
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