Home GPCR & G Protein Endothelin Receptor antagonist Zibotentan (ZD4054)

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Zibotentan (ZD4054) Endothelin Receptor antagonist

Cat.No.S1456

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

Chemical Structure

Molecular Weight: 424.43

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Quality Control

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

Chemical Information, Storage & Stability

Molecular Weight 424.43 Formula

C19H16N6O4S

 Storage (From the date of receipt)
CAS No. 186497-07-4 Download SDF Storage of Stock Solutions

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

Solubility

In vitro
Batch:

DMSO : 24 mg/mL (56.54 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
ET-A [1]
21 nM
In vitro
As Zibotentan (ZD4054) specifically inhibits ETA-mediated antiapoptotic effects, but not ETB-mediated proapoptotic effects in human and rat smooth muscle cells, this compound 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] 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] It also inhibits ET-1 induced EGFR transactivation in HEY and OVCA 433 cells. Moreover, it 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 (ZD4054) (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 this compound, 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). Its affinity 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.
In vivo
Zibotentan (ZD4054), administered 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. This effect is associated with the blocking of cell proliferation, as evaluated by 37% inhibition of Ki-67 expression, and 62% inhibition of tumor-induced vascularization. Consistently, treatment with this compound 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]
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

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

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