WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 203200
Description: An orally available selective antagonist of the endothelin-A (ET-A) receptor with potential antineoplastic activity. Zibotentan binds selectively to the ET-A receptor, thereby inhibiting endothelin-mediated mechanisms that promote tumor cell proliferation.
MedKoo Cat#: 203200
Name: Zibotentan (ZD4054 )
Chemical Formula: C19H16N6O4S
Exact Mass: 424.09537
Molecular Weight: 424.43
Elemental Analysis: C, 53.77; H, 3.80; N, 19.80; O, 15.08; S, 7.55
Synonym: ZD4054; ZD-4054; ZD 4054; Zibotentan.
IUPAC/Chemical Name: 2-(4-(1,3,4-oxadiazol-2-yl)phenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide
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)
SMILES Code: O=S(C1=CC=CN=C1C2=CC=C(C3=NN=CO3)C=C2)(NC4=NC=C(C)N=C4OC)=O
ZD4054 is a specific ETA receptor antagonist currently being evaluated in hormone-resistant prostate cancer in phase III clinical trials. In vitro, ZD4054 reversed ET-1-mediated inhibition of apoptosis in serum-deprived rat A10 and human VLTR-16 cells in a concentration-dependent manner. ZD4054 inhibited ET-1-mediated survival signaling pathways and decreased proliferation in ovarian OVCA 433 and HEY cells and in prostate PPC-1 and LAPC-4 cells. In A673 rhabdomyosarcoma cells, ET-1-induced phosphorylation of FAK, FAK, and paxillin was reversed with ZD4054, inhibiting the invasive phenotype mediated by these adhesion factors. In vivo, ZD4054 led to a significant reduction in tumor growth in animals bearing ovarian tumor xenografts, and significantly inhibited tumor angiogenesis. Pretreatment with ZD4054 also significantly delayed the onset of metastatic events after intracardiac injection of bladder TSU-Pr1-B1 cells in mice. These preclinical data show the potential anticancer effects of the specific blockade of the ETA receptor with ZD4054, supporting a program of clinical investigation. see http://www.ncbi.nlm.nih.gov/pubmed/19065106.
1: Dawson N, Payne H, Battersby C, Taboada M, James N. Health-related quality of life in pain-free or mildly symptomatic patients with metastatic hormone-resistant prostate cancer following treatment with the specific endothelin A receptor antagonist zibotentan (ZD4054). J Cancer Res Clin Oncol. 2010 Apr 14. [Epub ahead of print] PubMed PMID: 20390429.
2: Albiges L, Loriot Y, Gross-Goupil M, de La Motte Rouge T, Blesius A, Escudier B, Massard C, Fizazi K. [New drugs in metastatic castration-resistant prostate cancer]. Bull Cancer. 2010 Jan;97(1):149-59. French. PubMed PMID: 20022854.
3: Smollich M, GÃ¶tte M, FischgrÃ¤be J, Macedo LF, Brodie A, Chen S, Radke I, Kiesel L, WÃ¼lfing P. ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole. Breast Cancer Res Treat. 2009 Nov 27. [Epub ahead of print] PubMed PMID: 19943105.
4: Schelman WR, Liu G, Wilding G, Morris T, Phung D, Dreicer R. A phase I study of zibotentan (ZD4054) in patients with metastatic, castrate-resistant prostate cancer. Invest New Drugs. 2009 Sep 19. [Epub ahead of print] PubMed PMID: 19763400.
5: Fizazi K, Miller K. Specific endothelin-A receptor antagonism for the treatment of advanced prostate cancer. BJU Int. 2009 Nov;104(10):1423-5. Epub 2009 Jul 14. PubMed PMID: 19624592.
6: Swaisland HC, Oliver SD, Morris T, Jones HK, Bakhtyari A, Mackey A, McCormick AD, Slamon D, Hargreaves JA, Millar A, Taboada MT. In vitro metabolism of the specific endothelin-A receptor antagonist ZD4054 and clinical drug interactions between ZD4054 and rifampicin or itraconazole in healthy male volunteers. Xenobiotica. 2009 Jun;39(6):444-56. PubMed PMID: 19480550.
7: RosanÃ² L, Cianfrocca R, Masi S, Spinella F, Di Castro V, Biroccio A, Salvati E, Nicotra MR, Natali PG, Bagnato A. Beta-arrestin links endothelin A receptor to beta-catenin signaling to induce ovarian cancer cell invasion and metastasis. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2806-11. Epub 2009 Feb 6. PubMed PMID: 19202075; PubMed Central PMCID: PMC2650347.
8: Growcott JW. Preclinical anticancer activity of the specific endothelin A receptor antagonist ZD4054. Anticancer Drugs. 2009 Feb;20(2):83-8. Review. PubMed PMID: 19065106.
9: James ND, Caty A, Borre M, Zonnenberg BA, Beuzeboc P, Morris T, Phung D, Dawson NA. Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol. 2009 May;55(5):1112-23. Epub 2008 Nov 29. PubMed PMID: 19042080.
10: Warren R, Liu G. ZD4054: a specific endothelin A receptor antagonist with promising activity in metastatic castration-resistant prostate cancer. Expert Opin Investig Drugs. 2008 Aug;17(8):1237-45. Review. PubMed PMID: 18616419.