| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg | |||
| 500mg | |||
| Other Sizes |
Purity: ≥98%
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.
| Targets |
ET-A ( IC50 = 21 nM )
Endothelin A receptor (ET_A) (Ki = 0.44 nM, human; IC50 = 0.6 nM for ET-1 binding inhibition) [3][4] - Endothelin B receptor (ET_B) (Ki = 630 nM, human; >1400-fold lower affinity than ET_A) [3][4] - No significant affinity for other GPCRs (e.g., angiotensin II, VEGF receptors) (Ki > 10000 nM) [3] |
|---|---|
| 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]
Zibotentan (ZD4054) is a potent, highly selective endothelin A receptor (ET_A) antagonist, with minimal activity against ET_B [3][4] - In human prostate cancer (PC-3, DU145) cells, Zibotentan (1-20 μM) dose-dependently inhibited cell proliferation with IC50 values of 3.2 μM and 4.5 μM, respectively, and induced apoptosis via caspase-3 activation (apoptosis rate up to 40% at 20 μM) [1][3] - In human breast cancer (MDA-MB-231) cells, Zibotentan (5-15 μM) reduced cell migration by 55-70% and blocked ET-1-mediated invasion through Matrigel [4] - In human umbilical vein endothelial cells (HUVECs), Zibotentan (0.1-5 μM) inhibited ET-1-induced tube formation by 60-75% and endothelial cell proliferation by 45-60%, suppressing angiogenesis [2][3] - It had no significant effect on ET_B-mediated signaling in human bronchial smooth muscle cells at concentrations up to 100 μM, confirming subtype selectivity [3] |
| 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]
In nude mice bearing PC-3 prostate cancer xenografts, oral Zibotentan (1-10 mg/kg/day for 28 days) dose-dependently reduced tumor volume by 35-65% and increased intratumoral apoptosis (TUNEL-positive cells) by 2.3-3.5 fold [1][3] - In BALB/c mice with MDA-MB-231 breast cancer lung metastasis, Zibotentan (5 mg/kg/day, p.o.) inhibited lung metastatic nodule formation by 60% [4] - In a rat Matrigel plug angiogenesis model, Zibotentan (3 mg/kg/day, p.o.) reduced blood vessel density in plugs by 58% [2] - In PC-3 xenograft mice, Zibotentan (10 mg/kg/day) downregulated tumor tissue ET_A expression and suppressed Akt phosphorylation, inhibiting tumor angiogenesis [3] |
| Enzyme Assay |
The inhibition by Zibotentan (varying concentrations) of 125 iodine-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 125 iodine-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.
ET_A/ET_B receptor binding assay: Membrane preparations from human ET_A/ET_B-expressing cells were incubated with [¹²⁵I]-ET-1 (0.1 nM) and Zibotentan (0.001-1000 nM) at 25°C for 90 minutes. Non-specific binding was determined with excess unlabeled ET-1. Bound ligands were separated by filtration, and radioactivity was quantified to calculate Ki values [3][4] - GPCR selectivity assay: Zibotentan (1 μM) was incubated with a panel of 40+ GPCRs (including angiotensin II type 1, VEGF-R2) at 25°C for 60 minutes. Receptor binding was measured by radioactive ligand displacement assay to assess off-target activity [3] |
| 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.
Tumor cell proliferation assay: PC-3/DU145/MDA-MB-231 cells were seeded in 96-well plates, treated with Zibotentan (0.1-50 μM) for 72 hours. Cell viability was measured by MTT assay, and IC50 values were calculated [1][3][4] - Apoptosis assay: PC-3 cells were treated with Zibotentan (5-20 μM) for 48 hours, stained with annexin V-FITC and propidium iodide, and apoptosis rate was analyzed by flow cytometry. Caspase-3 activity was measured by colorimetric assay [1][3] - Endothelial tube formation assay: HUVECs were seeded on Matrigel-coated plates, treated with Zibotentan (0.1-5 μM) plus ET-1 (10 nM) for 12 hours. Tube formation was quantified by counting branch points [2][3] - Tumor cell invasion assay: MDA-MB-231 cells were pretreated with Zibotentan (5-15 μM) for 30 minutes, added to Matrigel-coated Transwell upper chambers, and ET-1 (10 nM) was added to lower chambers. Invaded cells were counted after 24 hours [4] |
| 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 PC-3 prostate cancer xenograft model: Male nude mice (18-22 g) were subcutaneously inoculated with PC-3 cells (5×10⁶ cells/mouse). When tumors reached 100 mm³, Zibotentan suspended in 0.5% CMC-Na was administered orally at 1, 3, 10 mg/kg/day for 28 days. Tumor volume, weight, apoptosis, and angiogenesis were evaluated [1][3] - MDA-MB-231 breast cancer metastasis model: Female BALB/c nude mice (18-22 g) were intravenously injected with MDA-MB-231 cells (2×10⁶ cells/mouse). Zibotentan (5 mg/kg/day) suspended in 0.5% CMC-Na was administered orally for 21 days. Lung metastatic nodules were counted [4] - Rat Matrigel plug angiogenesis model: Male Sprague-Dawley rats (200-250 g) were subcutaneously implanted with Matrigel plugs containing ET-1 (50 ng/plug). Zibotentan (3 mg/kg/day) suspended in 0.5% CMC-Na was administered orally for 14 days. Blood vessel density in plugs was analyzed by immunohistochemistry [2] |
| ADME/Pharmacokinetics |
Oral bioavailability: Approximately 85% in rats after oral administration; approximately 78% in dogs after oral administration [3]
- Elimination half-life: 12.5 hours in rats; 18.8 hours in dogs [3] - Plasma protein binding: 98.5% in human plasma (concentration range: 0.1-10 μg/mL) [3] - Distribution: Volume of distribution (Vd) in rats = 2.3 L/kg, widely distributed in tumor tissues and vascular beds [3] |
| Toxicity/Toxicokinetics |
Acute toxicity: Oral LD50 in rats > 500 mg/kg; in mice > 400 mg/kg [3]
- Subchronic toxicity (oral administration in rats over 28 days): No significant hepatotoxicity or nephrotoxicity was observed at doses up to 30 mg/kg/day; mild transient hypotension (mean arterial pressure decrease ≤10%) occurred at 50 mg/kg/day [3] - No significant changes in serum creatinine, BUN, ALT/AST or hematological parameters at therapeutic doses [3][4] - Preclinical studies have shown that this product has no significant drug interaction with chemotherapy drugs (e.g., docetaxel) [1] |
| References | |
| Additional Infomation |
N-(3-methoxy-5-methyl-2-pyrazinyl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]-3-pyridinesulfonamide is a phenylpyridine compound. Zibotentan is an orally administered selective endothelin A (ET-A) receptor antagonist with potential antitumor activity. Zibotentan selectively binds to the ET-A receptor, thereby inhibiting the endothelin-mediated mechanism that promotes tumor cell proliferation.
Drug indications It is being investigated for the treatment of prostate cancer. Zibotentan (ZD4054) is a potent and highly selective ET_A receptor antagonist that has been developed for the treatment of solid tumors[1][3][4]. - Its core mechanism is to block the binding of ET-1 to the ET_A receptor, thereby inhibiting downstream signaling pathways (Akt, ERK1/2) involved in tumor cell proliferation, survival, angiogenesis, and metastasis[3][4]. - Research applications include inhibiting tumor growth and metastasis in prostate cancer, breast cancer, and other ET_A-overexpressing solid tumors [1][4]. - High selectivity for ET_A rather than ET_B minimizes off-target effects (e.g., gastrointestinal dysfunction). Use of non-selective endothelin receptor antagonists [3] - They exert their antitumor effects primarily by inhibiting tumor angiogenesis and directly inducing tumor cell apoptosis [1][3]. |
| Molecular Formula |
C19H16N6O4S
|
|
|---|---|---|
| Molecular Weight |
424.43
|
|
| Exact Mass |
424.095
|
|
| Elemental Analysis |
C, 53.77; H, 3.80; N, 19.80; O, 15.08; S, 7.55
|
|
| CAS # |
186497-07-4
|
|
| Related CAS # |
|
|
| PubChem CID |
9910224
|
|
| Appearance |
White to off-white solid powder
|
|
| Density |
1.4±0.1 g/cm3
|
|
| Boiling Point |
637.0±65.0 °C at 760 mmHg
|
|
| Flash Point |
339.0±34.3 °C
|
|
| Vapour Pressure |
0.0±1.9 mmHg at 25°C
|
|
| Index of Refraction |
1.628
|
|
| LogP |
2.38
|
|
| Hydrogen Bond Donor Count |
1
|
|
| Hydrogen Bond Acceptor Count |
10
|
|
| Rotatable Bond Count |
6
|
|
| Heavy Atom Count |
30
|
|
| Complexity |
654
|
|
| Defined Atom Stereocenter Count |
0
|
|
| SMILES |
O=S(NC1=NC=C(C)N=C1OC)(C2=CC=CN=C2C3=CC=C(C4=NN=CO4)C=C3)=O
|
|
| 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 |
|
|
| 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 (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.89 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 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.
Calculation results
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.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
A Study to Assess Zibotentan Pharmacokinetics in Participants With Moderate Hepatic and Moderate Renal Impairment
CTID: NCT05112419
Phase: Phase 1 Status: Completed
Date: 2022-01-27
|
|
|
|
|
|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
