ARN-509

Androgen receptor inhibitor CAS# 956104-40-8

ARN-509

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Chemical structure

ARN-509

3D structure

Chemical Properties of ARN-509

Cas No. 956104-40-8 SDF Download SDF
PubChem ID 24872560 Appearance Powder
Formula C21H15F4N5O2S M.Wt 477.43
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Apalutamide
Solubility DMSO : ≥ 83.3 mg/mL (174.48 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide
SMILES CNC(=O)C1=C(C=C(C=C1)N2C(=S)N(C(=O)C23CCC3)C4=CN=C(C(=C4)C(F)(F)F)C#N)F
Standard InChIKey HJBWBFZLDZWPHF-UHFFFAOYSA-N
Standard InChI InChI=1S/C21H15F4N5O2S/c1-27-17(31)13-4-3-11(8-15(13)22)30-19(33)29(18(32)20(30)5-2-6-20)12-7-14(21(23,24)25)16(9-26)28-10-12/h3-4,7-8,10H,2,5-6H2,1H3,(H,27,31)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of ARN-509

DescriptionARN-509 is a selective and competitive inhibitor of androgen receptor with an IC50 value of 16 nM.
TargetsAndrogen ReceptorGABAA receptor    
IC5016 nM3 μM    

Protocol

Kinase Assay [1]
Competitor assay kits (green) are used to determine relative in vitro binding affinities of ARN-509 for the rat AR ligand binding domain (LBD), human progesterone receptor (PR) LBD, and full-length human estrogen receptor-alpha (ERα) and human glucocorticoid receptor (GR). Each hormone dose is performed in triplicate, relative error is calculated from the standard error of the mean (SEM), and binding curves are fit using a single binding site competition model (Prism statistical analysis software package) with R2>0.8. Experiments are conducted multiple times with SEM<0.3 log units from the average logIC50 value. Ki values are calculated as averages across experiments with SEM, and binding affinities are reported as a percentage relative to the tight-binding ligand control for that receptor[1].

Cell Assay [1]
Trypsinized VCaP cells are adjusted to a concentration of 100,000 cells per mL in phenol-red-free RPMI 1640 (with 5% CSS), and dispensed in 16 µL aliquots into CellBIND 384 well plates. Cells are incubated for 48 hours, after which ligand is added in a 16 µL volume to the RPMI culture medium. For the antagonist mode assay, the ligands are diluted in culture medium also containing 30 pM R1881. After 7 days’ incubation, 16 µL of CellTiter-Glo Luminescent Cell Viability Assay is added and Relative Luminescence Units (RLUs) measured[1].

Animal Administration [1]
Mice[1] In vivo xenograft experiments to determine anti-tumor response are carried out in SHO SCID male mice. Mice are orchiectomized under isoflorane anesthesia and are given 2-3 days to recover prior to tumor cell injection. LNCaP/AR(cs) cells are suspended in 50% RPMI, 50% Matrigel, and 5×106 cells/xenograft are injected in a volume of 100 μL. Animals are observed weekly until tumor growth is apparent. From 24 d post-injection, tumors are measured weekly, and after 40-60 days post-injection, animals are randomized into cohorts of equivalent mean (150-250 mm3) and range tumor burden. All compounds (e.g., ARN-509, 30 mg/kg per day) are administered daily by oral gavage. Statistical analyses are performed using Graphpad Prism.

References:
[1]. Clegg NJ, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012 Mar 15;72(6):1494-503. [2]. Smith MR, et al. Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort. Eur Urol. 2016 May 6. pii: S0302-2838(16)30133

ARN-509 Dilution Calculator

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Preparing Stock Solutions of ARN-509

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0945 mL 10.4727 mL 20.9455 mL 41.891 mL 52.3637 mL
5 mM 0.4189 mL 2.0945 mL 4.1891 mL 8.3782 mL 10.4727 mL
10 mM 0.2095 mL 1.0473 mL 2.0945 mL 4.1891 mL 5.2364 mL
50 mM 0.0419 mL 0.2095 mL 0.4189 mL 0.8378 mL 1.0473 mL
100 mM 0.0209 mL 0.1047 mL 0.2095 mL 0.4189 mL 0.5236 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on ARN-509

ARN-509, a synthetic biaryl thiohydantoin compound, is a competitive androgen receptor (AR) inhibitor and fully antagonistic to AR overexpression. The IC50 of ARN-509 is 16 nmol/L [1].
AR, included in the steroid receptor superfamily, is important for prostate cell proliferation and male sexual differentiation [2]. AR overexpression is a common and important feature of castration resistant prostate cancer (CRPC) [1].
ARN-509 (1 μmol/L) treatment for 48 hours resulted in increased DNA damage in LNCaP cells, LNCaP-AR cells and VCaP cells. In LNCaP cell line, treatment with ARN-509 (1 μmol/L) resulted in decreased cell survival. Treatment with ARN-509 (1 μmol/L) for 48 hours significantly decreased C-NHEJ–mediated recombination (>60%) in LNCaP cells that had been transfected with V(D)J recombination substrate along with RAG1 and RAG2 expression vectors [3]. ARN-509 showed robust transcriptional and proliferative agonist activity in AR F876L–expressing cells, and promoted AR DNA binding in LNCaP/SRαF876L cells [4].
Orally treated with ARN-509 (10 mg/kg/d) for 17 days, androgendriven luciferase reporter–gene activity in castrate male immunodeficient mice harboring LNCaP/AR-luc xenograft tumors (coexpressing exogenous AR and the AR-dependent reporter ARR2-Pb-luc), was consistently reduced. This indicated that ARN-509 inhibited AR in vivo. ARN-509 made tumors exhibit a decrease in proliferative index and an increase in apoptotic rate [1].
References:
[1]. Nicola J. Clegg, John Wongvipat, James D. Joseph, et al. ARN-509: A Novel Antiandrogen for Prostate Cancer Treatment. Therapeutics, Targets & Chemical Biology, 2012, 72(6): 1494-1503.
[2]. Shuyuan Yeh and Chawnshang Chang. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc. Natl. Acad. Sci., 1996, 93: 5517-5521.
[3]. William R. Polkinghorn, Joel S. Parker, Man X. Lee, et al. Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers. Cancer Discovery, 2013, 3(11):1245-53.
[4]. James D. Joseph, Nhin Lu, Jing Qian, et al. A Clinically Relevant Androgen Receptor Mutation Confers Resistance to Second-Generation Antiandrogens Enzalutamide and ARN-509. Cancer Discovery, 2013, 3(9):1020-9.

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References on ARN-509

Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer.[Pubmed:24002508]

J Clin Oncol. 2013 Oct 1;31(28):3525-30.

PURPOSE: ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC. PATIENTS AND METHODS: Thirty patients with progressive CRPC received continuous daily oral ARN-509 at doses between 30 and 480 mg, preceded by administration of a single dose followed by a 1-week observation period with pharmacokinetic sampling. Positron emission tomography/computed tomography imaging was conducted to monitor [(18)F]fluoro-alpha-dihydrotestosterone (FDHT) binding to AR in tumors before and during treatment. Primary objective was to determine pharmacokinetics, safety, and recommended phase II dose. RESULTS: Pharmacokinetics were linear and dose proportional. Prostate-specific antigen declines at 12 weeks (>/= 50% reduction from baseline) were observed in 46.7% of patients. Reduction in FDHT uptake was observed at all doses, with a plateau in response at >/= 120-mg dose, consistent with saturation of AR binding. The most frequently reported adverse event was grade 1/2 fatigue (47%). One dose-limiting toxicity event (grade 3 abdominal pain) occurred at the 300-mg dose. Dose escalation to 480 mg did not identify a maximum-tolerated dose. CONCLUSION: ARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.

Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort.[Pubmed:27160947]

Eur Urol. 2016 Dec;70(6):963-970.

BACKGROUND: Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. OBJECTIVE: To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). DESIGN, SETTING, AND PARTICIPANTS: We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] >/=8 ng/ml or PSA doubling time [PSA DT] /=50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo-not reached [NR]); median MFS was NR (95% CI, 33.4 mo-NR). Most of the patients discontinued study treatment (n=33) due to disease progression (n=11 [22%]) or adverse events (AEs) (n=9 [18%]). The most common AE was fatigue (any grade, n=31 [61%]) although grade >/=3 fatigue was uncommon (n=2 [4%]). These represent the first apalutamide nmCRPC patient clinical data. CONCLUSIONS: In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control. PATIENT SUMMARY: Antitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01171898.

Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone.[Pubmed:28213364]

Clin Cancer Res. 2017 Jul 15;23(14):3544-3551.

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC).Experimental Design: Two cohorts were studied: AAP-naive and post-AAP patients who had received >/=6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was >/=50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment.Results: Forty-six patients enrolled in the AAP-naive (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months-not reached) and 3.7 months (95% CI, 2.8-5.6 months), and median time on treatment 21 months (range, 2.6-37.5) and 4.9 months (range, 1.3-23.2), for the AAP-naive and post-AAP cohorts, respectively. Eighty percent (95% CI, 59-93) and 64% (95% CI, 43-82) of AAP-naive and 43% (95% CI, 22-66) and 10% (95% CI, 1-30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain.Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naive and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544-51. (c)2017 AACR.

Description

Apalutamide (ARN-509) is a potent and competitive androgen receptor (AR) antagonist, binding AR with an IC50 of 16 nM.

Keywords:

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