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Description of ARN-509: ARN-509, also known as JNJ-56021927, is an androgen receptor antagonist with potential antineoplastic activity. ARN-509 binds to AR in target tissues thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus. This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)
ARN-509, being develop by Aragon Pharmaceuticals, is currently in a Phase I clinical trial being conducted at Memorial Sloan-Kettering Cancer Center (New York). The open-label, dose-escalation study will determine the safety and tolerability in patients with castration-resistant prostate cancer.
Current developer: Aragon Pharmaceuticals
Note: The technical data provided above is for guidance only. For batch specific data refer to the Certificate of Analysis.
Protocols from literature
The chemical structure of ARN-509 is very similar structure to that of Enzalutamide (MDV3100) with two minor modifications: (a) two methyl groups in the 5-member ring of MDV3100 is linked by a CH2 group in ARN-509; (b) the carbon atom in the benzene ring of MDV3100 is replaced by a nitrogen atom in ARN-509. ARN-509 is considered as a Me-Too drug of Enzalutamide (MDV3100). ARN-509 was claimed to be more active than Enzalutamide (MDV3100).
ARN-509 is a novel 2nd Generation anti-androgen that is targeted to treat castration resistant prostate cancers where 1st generation anti-androgens fail. ARN-509 is unique in its action in that it inhibits both AR nuclear translocation and AR binding to androgen response elements in DNA. Importantly, and in contrast to the first-generation anti-androgen bicalutamide, it exhibits no agonist activity in prostate cancer cells that over-express AR. ARN-509 is easily synthesized, and its oral bioavailability and long half-life allow for once-daily oral dosing. In addition, its excellent preclinical safety profile makes it well suited as either a mono- or a combination therapy across the entire spectrum of prostate cancer disease states. (source: http://www.aragonpharm.com/programs/arn509.htm).
ARN-509 is a
competitive AR inhibitor, which is fully antagonistic to AR
overexpression, a common and important feature of CRPC.
optimized for inhibition of AR transcriptional activity and prostate
cancer cell proliferation, pharmacokinetics and in vivo efficacy. In
contrast to bicalutamide,
significant agonist activity in preclinical models of CRPC. Moreover,
inducing activity for AR nuclear localization or DNA binding. In a
clinically valid murine xenograft model of human CRPC,
greater efficacy than MDV3100. Maximal therapeutic response in this
model was achieved at 30 mg/kg/day of
whereas the same response required 100 mg/kg/day of MDV3100 and higher
steady-state plasma concentrations. Thus,
exhibits characteristics predicting a higher therapeutic index with a
greater potential to reach maximally efficacious doses in man than
current AR antagonists. Our findings offer preclinical proof of
principle for ARN-509
as a promising therapeutic in both castration-sensitive and
castration-resistant forms of prostate cancer. (source: Cancer
Res. 2012 Jan 20. [Epub ahead of print])
(source: Cancer Res. 2012 Jan 20. [Epub ahead of print])
1: Clegg NJ, Wongvipat J, Tran C, Ouk S, Dilhas A, Joseph J, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones PM, Klang M, Smith ND, de Stanchina E, Wu N, Ouerfelli O, Rix P, Heyman R, Jung ME, Sawyers CL, Hager JH. ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer Res. 2012 Mar 15;72(6):1494-1503. Epub 2012 Jan 20.PubMed PMID: 22266222.
2. Preparation of spiro thiohydantoin compounds as
androgen receptor modulators By Smith, Nicholas D.; Bonnefous, Celine;
Julien, Jackaline D. From PCT Int. Appl. (2011), WO 2011103202 A2
(Keyword; CAS#; MedKoo Cat#)
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