Zibotentan (ZD4054)

Alias: ZD4054; ZD-4054; ZD 4054
Cat No.:V1508 Purity: ≥98%
Zibotentan (formerly known as ZD-4054; ZD4054) is a specific and orally bioavailable Endothelin (ET)A antagonist with potential antitumor activity.
Zibotentan (ZD4054) Chemical Structure CAS No.: 186497-07-4
Product category: Endothelin Receptor
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Zibotentan (formerly known as ZD-4054; ZD4054) is a specific and orally bioavailable Endothelin (ET)A antagonist with potential antitumor activity. It shows no action against ETB and has an IC50 of 21 nM for inhibiting the endothelin receptor. The FDA approved zibotentan for prostate cancer treatment on a fast track basis; however, the drug did not pass clinical trials. By selectively binding to the ET-A receptor, zibotentan blocks the actions of endothelin that stimulate the growth of tumor cells. By blocking AKT and p42/44MAPK phosphorylation, ZD4054 successfully reduced basal and ET-1-induced cell proliferation. It also enhanced apoptosis by blocking Bcl-2, activating caspase-3, and poly(ADP-ribose) polymerase protein.

Biological Activity I Assay Protocols (From Reference)
Targets
ET-A ( IC50 = 21 nM )
ln Vitro

In vitro activity: Zibotentan binds to endothelin A receptor (ETA) with high affinity (Ki of 13 nM) and has no affinity for endothelin B receptor (ETB) (IC50 of >10 μM). This is because it specifically inhibits ETA-mediated antiapoptotic effects but not ETB-mediated proapoptotic effects in human and rat smooth muscle cells.[1] Treatment with zibotentan at a concentration of 1 μM inhibits the mitogenic activity induced by ET-1 in the ovarian carcinoma cell lines HEY and OVCA 433, which secrete ET-1 and express ETA and ETB mRNA.[2] In HEY and OVCA 433 cells, ZD4054 (1 μM) inhibits ET-1-induced EGFR transactivation. Zibotentan (1 μM) reverses the epithelial-mesenchymal transition (EMT) mediated by ET-1 by upregulating the expression and promoter activity of E-cadherin and blocking the secretion of vascular endothelial growth factor (VEGF) and invasiveness in HEY and OVCA 433 cells.[3] Additionally, zibotentan significantly reduces the basal and ET-1-induced proliferation of cells in SKOV-3 and A-2780 cells. This is linked to phosphorylation of AKT and p42/44MAPK as well as increased apoptosis via bcl-2 inhibition and activation of caspase-3 and poly(ADP-ribose) polymerase proteins.[4]

ln Vivo
Zibotentan potently suppresses the growth of HEY ovarian carcinoma xenografts in mice by 69% while posing no toxicity, when administered at a dose of 10 mg/kg/day for 21 days. This effect is correlated with a 37% reduction in Ki-67 expression, a 62% inhibition of tumor-induced vascularization, and a blocking of cell proliferation. Zibotentan treatment consistently and potently increases the expression of E-cadherin while significantly inhibiting the expression of matrix mETAlloproteinase-2 (MMP-2) and VEGF, as well as the activation of p42/44 MAPK and EGFR. [3]
Enzyme Assay
The inhibition by Zibotentan (varying concentrations) of 125iodine-ET-1 binding to cloned human ETA is assessed using standard radioligand-binding techniques. Mice erythroleukaemic cells are used to express human recombinant ETA, and cell membranes are prepared for competitive binding experiments using 125iodine-ET-1 as the radioligand. In vitro experiments with Zibotentan are conducted in triplicate, ranging from 100 pM to 100 μM in half-log increments. The expression used to quantify the inhibition of ET-1 binding is the geometric mean pIC50 value, which represents the concentration required to inhibit 50% of binding, along with a 95% confidence interval (CI). Zibotentan's affinity for cloned human ETA is evaluated by applying Cheng and Prusoff's equation to find the equilibrium dissociation constant (Ki) in an additional receptor-binding screen that makes use of more concentration-response curves from three different studies.
Cell Assay
After a 24-hour incubation period in serum-free DMEM, cells are subjected to a 48-hour Zibotentan exposure. Following therapy, cells are lysed, the supernatant is extracted, and using a microplate reader, the assay is performed to look for histone-associated DNA fragments at 405 nm. Adherent and floating cells are collected for the purpose of detecting early apoptotic events. Using the Vybrant Apoptosis Kit, cells are double stained with propidium iodide and FITC-conjugated Annexin V. Their cytofluorometric analysis is then performed right away.
Animal Protocol
Dissolved in DMSO, and diluted in PBS; 10 mg/kg; i.p. injection
Female athymic (nu+/nu+) mice bearing established HEY human ovarian carcinoma xenografts
References

[1]. Br J Cancer . 2005 Jun 20;92(12):2148-52.

[2]. Exp Biol Med (Maywood) . 2006 Jun;231(6):1132-5.

[3]. Cancer Res . 2007 Jul 1;67(13):6351-9.

[4]. Mol Cancer Ther . 2007 Jul;6(7):2003-11.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C19H16N6O4S
Molecular Weight
424.43
Exact Mass
424.1
Elemental Analysis
C, 53.77; H, 3.80; N, 19.80; O, 15.08; S, 7.55
CAS #
186497-07-4
Appearance
Solid powder
SMILES
CC1=CN=C(C(=N1)OC)NS(=O)(=O)C2=C(N=CC=C2)C3=CC=C(C=C3)C4=NN=CO4
InChi Key
FJHHZXWJVIEFGJ-UHFFFAOYSA-N
InChi Code
InChI=1S/C19H16N6O4S/c1-12-10-21-17(19(23-12)28-2)25-30(26,27)15-4-3-9-20-16(15)13-5-7-14(8-6-13)18-24-22-11-29-18/h3-11H,1-2H3,(H,21,25)
Chemical Name
N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide
Synonyms
ZD4054; ZD-4054; ZD 4054
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 24~25 mg/mL (56.5~58.9 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In Vivo)
1%DMSO+30% polyethylene glycol+1%Tween 80: 30 mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.3561 mL 11.7805 mL 23.5610 mL
5 mM 0.4712 mL 2.3561 mL 4.7122 mL
10 mM 0.2356 mL 1.1781 mL 2.3561 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00713791 Completed Drug: ZD4054 Healthy AstraZeneca June 2008 Phase 1
NCT00672581 Completed Drug: ZD4054 Hepatic Impairment AstraZeneca April 2008 Phase 1
NCT00709553 Completed Drug: midazolam
Drug: ZD4054
Healthy AstraZeneca July 2008 Phase 1
NCT00710047 Completed Drug: ZD4054 Healthy Volunteers AstraZeneca June 2008 Phase 1
NCT00713336 Completed Drug: ZD4054
Drug: ZD4054 Placebo
Healthy AstraZeneca June 2008 Phase 1
Biological Data
  • Administration of ZD4054 (10 and 30 mg) to healthy volunteers inhibits ET-1 induced vasoconstriction. Br J Cancer . 2005 Jun 20;92(12):2148-52.
  • Administration of ZD4054 at doses upto 240 mg has no effect on plasma ET-1 concentrations in healthy volunteers at 4 (A) and 24 h (B) post-dose. Br J Cancer . 2005 Jun 20;92(12):2148-52.
  • Effects of ZD4054 and/or gefitinib on ET-1–induced EGFR, AKT, and p42/44 MAPK activation and cell proliferation in ovarian cancer cells. Cancer Res . 2007 Jul 1;67(13):6351-9.
  • ZD4054 reverts EMT, and restores E-cadherin expression and promoter activity and invasiveness in ovarian cancer cells. Cancer Res . 2007 Jul 1;67(13):6351-9.
  • Effect of ZD4054 in monotherapy and combination therapy with paclitaxel on ovarian carcinoma cell proliferation and on MAPK and AKT signaling pathways. Mol Cancer Ther . 2007 Jul;6(7):2003-11.
  • Induction of apoptosis by treatment with ZD4054 and paclitaxel in ovarian carcinoma cells. Mol Cancer Ther . 2007 Jul;6(7):2003-11.
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