Zibotentan (ZD4054) is a more selective and specific endothelin-A receptor (ETAR) antagonist with an IC50 value of 21 nM. Zibotentan inhibits endothelin-1 (ET-1) mediated processes associated with cancer progression, including invasion, metastasis, and angiogenesis. Zibotentan has no demonstrable effect on the endothelin-B receptor (ETBR), which promotes apoptosis (cell death). It is intended to be used in combination with docetaxel as an addition to standard chemotherapy for patients with metastatic CRPC. Zibotentan (ZD4054) has been shown to compete with 125I-ET-1 for binding to the cloned human ETA-receptor in vitro. Zibotentan treatment produced significant inhibition of tumor growth in ovarian and breast xenografts.
| Cell Experiment | |
|---|---|
| Cell lines | OVCA 433 and HEY cells |
| Preparation method | Cell proliferation assay. [3H]thymidine incorporation was measured as previously described ( 5). Cells were seeded in 96-well plates at ∼80% confluence (2 × 106 per well) and incubated in serum-free medium for 24 h to induce quiescence and 100 nmol/L ET-1 was added. Responses to all treatments were assayed in sextuplicate, and results were expressed as the means of three separate experiments. |
| Concentrations | 1 μmol/L |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | HEY cells Xenografts in nude mice |
| Formulation | diluted in PBS |
| Dosages | 10 mg/kg/d for 21 days |
| Administration | i.p. |
| Molecular Weight | 424.43 |
| Formula | C19H16N6O4S |
| CAS Number | 186497-07-4 |
| Solubility (25°C) | DMSO 18 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related Endothelin Receptor Products |
|---|
| Endothelin 1 (swine, human) (TFA)
Endothelin 1 (swine, human) (TFA) is a synthetic peptide with the sequence of human and swine Endothelin 1, which is a potent endogenous vasoconstrictor. |
| Atrial Natriuretic Peptide (ANP) (1-28), rat
Atrial Natriuretic Peptide (ANP) (1-28), rat is a major circulating form of ANP in rats, potently inhibits Angiotensin II (Ang II)-stimulated endothelin-1 secretion in a concentration-dependent manner. |
| [Asn18] Endothelin-1, human
[Asn18] Endothelin-1, human is a peptide. |
| [Lys4] Sarafotoxin S6c
[Lys4] Sarafotoxin S6c, a sarafotoxin analogue, is a potent and partial agonist of endothelin receptor. |
| [Ala2] Endothelin-3, human
[Ala2] Endothelin-3, human is a linear analog of endothelin-3 (ET-3) where substitution of Ala for Cys residues. |
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