Zibotentan (ZD4054)
Catalog No.S1456
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.
Cited by 2 Publications
1 Customer Review
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(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.
Purity & Quality Control
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Biological Activity
| Description | 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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| 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] |
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| 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
| 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. |
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| Cell Research:[3] |
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| Animal Research:[3] |
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Solubility (25°C)
| In vitro | DMSO | 24 mg/mL (56.54 mM) |
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| 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 |
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| Formula | C19H16N6O4S |
| CAS No. | 186497-07-4 |
| Storage | powder |
| in solvent | |
| Synonyms | N/A |
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Clinical Trial Information
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT02047708 | Completed | Scleroderma|Scleroderma Renal Crisis|Chronic Kidney Disease | University College London|Medical Research Council | October 2014 | Phase 2 |
| NCT01890135 | Completed | Peripheral Arterial Disease|Intermittent Claudication | University of Virginia|National Institutes of Health (NIH) | June 2013 | 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 |
| NCT00997945 | Completed | Advanced Solid Malignancies | AstraZeneca | October 2009 | Phase 1 |
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