Molecular Weight(MW): 424.43
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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|Description||Zibotentan (ZD4054) is a specific Endothelin (ET)A antagonist with IC50 of 21 nM, exhibiting no activity at ETB. Phase 3.|
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.  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.  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.  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. 
|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. |
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.
|In vitro||DMSO||24 mg/mL (56.54 mM)|
|In vivo||1% DMSO+30% polyethylene glycol+1% Tween 80||30 mg/mL|
* 1 mg/ml means slightly soluble or insoluble.
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Clinical Trial Information
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT02047708||Recruiting||Scleroderma|Scleroderma Renal Crisis|Chronic Kidney Disease||University College, London|Medical Research Council||October 2014||Phase 2|
|NCT01890135||Recruiting||Peripheral Arterial Disease|Intermittent Claudication||University of Virginia|National Institutes of Health (NIH)||June 2013||Phase 2|
|NCT01134497||Not yet recruiting||Metastatic Breast Cancer||Cardiff University||September 2010||Phase 2|
|NCT01119118||Terminated||Prostate Cancer||University of Wisconsin, Madison|AstraZeneca||April 2010||Phase 2|
|NCT01205711||Completed||Colorectal Cancer||Cardiff University||April 2010||Phase 2|
|NCT01000948||Terminated||Prostate Cancer|Metastasis||Aarhus University Hospital|Rigshospitalet, Denmark||October 2009||Phase 2|
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