ARN-509
(Synonyms: 阿帕鲁胺,ARN 509; ARN509, Apalutamide) 目录号 : GC16840
ARN-509是一种合成的双芳基硫代乙内酰脲化合物，抑制雄激素受体（AR），IC50值为16nM。
Cas No.:956104-40-8
Sample solution is provided at 25 µL, 10mM.
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ARN-509 is a synthetic biaryl thiohydantoin compound that inhibits androgen receptor (AR), with an IC50 value of 16nM[1]. ARN-509 irreversibly binds to the ligand binding domain of the AR with high affinity, induces conformational changes in AR, hinders the translocation of the receptor complex to the nucleus, and thereby prevents its binding to androgen response elements[2]. ARN-509 has been widely used in the related research on prostate cancer treatment[3].
In vitro, ARN-509 treatment (100μM; 24h) significantly inhibited the proliferation of 22Rv1 cells, and suppressed nuclear entry of AR, AR-V7, and phosphorylated AR[4]. Treatment with 10μM ARN-509 significantly inhibited AR signal transduction in LNCaP prostate cancer cell lines, resulting in reduced cell proliferation[1].
In vivo, ARN-509 treatment through oral gavage at a dose of 30mg/kg/day for 60 weeks, which significantly reduced the incidence of prostate cancer induced by N-methyl-N-nitrosourea in male Wistar rats[5]. In the LNCaP/AR castration-resistant prostate cancer (CRPC) mouse model, an oral administration dose of 10mg/kg/day of ARN-509 can significantly inhibit tumor regression[6]. In genetically engineered mouse prostate cancer (GEM-PCa) models, four weeks of oral treatment with ARN-509 (30mg/kg/day) significantly reduced tumor burden by 33.5% and increased PI3K-AKT signaling[7].
References:
[1]Clegg N J, Wongvipat J, Joseph J D, et al. ARN-509: a novel antiandrogen for prostate cancer treatment[J]. Cancer research, 2012, 72(6): 1494-1503.
[2]Smith M R, Antonarakis E S, Ryan C J, 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[J]. European urology, 2016, 70(6): 963-970.
[3]Smith M R, Antonarakis E S, Ryan C J, et al. ARN-509 in men with high risk non-metastatic castration-resistant prostate cancer[J]. Annals of Oncology, 2012, 23: ix303.
[4]Koukourakis M I, Kakouratos C, Kalamida D, et al. Comparison of the effect of the antiandrogen apalutamide (ARN-509) versus bicalutamide on the androgen receptor pathway in prostate cancer cell lines[J]. Anti-cancer drugs, 2018, 29(4): 323-333.
[5]Murillo G, Peng X, Muzzio M, et al. Exceptional activity of ARN-509 (apalutamide) in prostate cancer prevention in rats[J]. Cancer Research, 2019, 79(13_Supplement): 2730-2730.
[6]Hager J H, Smith N D, Bischoff E, et al. Effect of the novel anti-androgen ARN-509 on response and seizure in castration-resistant prostate cancer models[J]. Journal of Clinical Oncology, 2011, 29(7_suppl): 28-28.
[7]Velasco M A D, Nozawa M, Kura Y, et al. Apalutamide (ARN-509) demonstrates therapeutic efficacy in genetically engineered mouse models of Pten-deficient prostate cancer[J]. Cancer Research, 2018, 78(13_Supplement): 3737-3737.
ARN-509是一种合成的双芳基硫代乙内酰脲化合物，抑制雄激素受体（AR），IC50值为16nM[1]。ARN-509通过高亲和力不可逆地结合AR的配体结合域，诱导受体构象变化，阻碍受体复合物向细胞核的转运，从而阻止AR与雄激素反应元件的结合[2]。ARN-509已被广泛应用于前列腺癌治疗的相关研究中[3]。
在体外，ARN-509（100μM；24小时）处理能显著抑制22Rv1细胞的增殖，并阻断AR、AR-V7变体及磷酸化AR的核内转移[4]。10μM浓度的ARN-509处理可显著抑制LNCaP前列腺癌细胞系的AR信号传导，导致细胞增殖减少[1]。
在体内，ARN-509通过口服灌胃给药（30mg/kg/day)持续60周能显著降低雄性Wistar大鼠由N-甲基-N-亚硝基脲诱导的前列腺癌发生率[5]。在LNCaP/AR去势抵抗性前列腺癌（CRPC）小鼠模型中，每日10mg/kg剂量的ARN-509口服给药可显著抑制肿瘤进展[6]。在基因工程小鼠前列腺癌（GEM-PCa）模型中，ARN-509口服治疗（30mg/kg/day）持续4周，使肿瘤负荷显著降低33.5%，同时增强PI3K-AKT信号通路活性[7]。
| Cell experiment [1]: | |
Cell lines | 22Rv1 cells |
Preparation Method | 2.5×10322Rv1 cells were inoculated in each well on a 96-well plate and incubated for 24 hours to allow the cells to attach to the well surface. Then, the cells were exposed to ARN-509 (10, 50, and 100μM; 24h) and Testosterone (10μmol/L; 24h). The effects on cell viability were tested when the ARN-509 and Testosterone were continuously present in the culture medium. To assess cell viability, 10%v/v AlamarBlue was added to each well. As a negative control (background measurement), ARN-509 was not contained in the culture medium. Vitamin C (5μl/well) was used as the positive control to completely reduce rizulin. Seven hours later, the relative fluorescence (in RFU: fluorescence per well minus background fluorescence) was measured using the microplate reader. Measure every other day from day 0 (24 hours after sowing) to day 6. The experiments were conducted under normal hypoxia and 1% hypoxia conditions. |
Reaction Conditions | 10, 50, and 100μM; 24h |
Applications | ARN-509 significantly inhibited the viability of 22Rv1 cells in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | SHO male mice |
Preparation Method | The in vivo xenotransplantation experiment was conducted in male SHO mice. Mice had their testicles removed under isoflurane anesthesia and were given a recovery time of 7 to 10 days. LNCaP/AR (cs) cells were suspended in 50% RPMI and 50% Matrigel. 3×106 cells were injected into each xenograft, with a volume of 100μL. Observe the animals every week until the tumor grows significantly. Forty to 60 days after injection, the animals were randomly divided into cohorts with equal average tumor burden and range (150-250mm3). In all LNCaP/AR (cs) xenotransplantation studies, ARN-509 (30mg/kg) and enzalutamide active pharmaceutical ingredients were prepared in 18% PEG-400, 1% Tween-80 and 1% povidone, and in 15% vitamin E-TPGS and 65% 0.5% w/v CMC solution, all compounds were administered by oral gavage daily. After daily administration of ARN-509 for 60 days, the tumor growth in mice was analyzed. |
Dosage form | 30mg/kg/day for 60 days; p.o. |
Applications | ARN-509 treatment significantly suppressed tumor growth, and increased the survival rate of mice. |
References: | |
| Cas No. | 956104-40-8 | SDF | |
| 别名 | 阿帕鲁胺,ARN 509; ARN509, Apalutamide | ||
| 化学名 | 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 | ||
| Canonical 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 | ||
| 分子式 | C21H15F4N5O2S | 分子量 | 477.43 |
| 溶解度 | ≥ 23.85mg/mL in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0945 mL | 10.4727 mL | 20.9455 mL |
| 5 mM | 0.4189 mL | 2.0945 mL | 4.1891 mL |
| 10 mM | 0.2095 mL | 1.0473 mL | 2.0945 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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