ARQ-092
(Synonyms: Miransertib) 目录号 : GC19036
An orally bioavailable pan-Akt inhibitor
Cas No.:1313881-70-7
Sample solution is provided at 25 µL, 10mM.
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ARQ-092 is an orally bioavailable, selective, and potent allosteric Akt inhibitor with IC50s of 2.7 nM, 14 nM and 8.1 nM for Akt1, Akt2, Akt3, respectively.
ARQ-092 (Compound 21a) demonstrates high enzymatic potency against Akt1, Akt2 and Akt3, as well as potent cellular inhibition of Akt activation and the phosphorylation of the downstream target PRAS40. ARQ-092 shows strong affinity for un-phosphorylated fulllength Akt1 and potently inhibited the phosphorylated form of full-length Akt isoforms. In a large panel of cell lines derived from various tumor types, ARQ-092 shows potent anti-proliferative activity in cell lines containing PIK3CA/PIK3R1 mutations compared to those with wild-type (wt) PIK3CA/PIK3R1 or PTEN loss. ARQ-092 shows excellent inhibition of p-Akt (S473) and p-Akt (T308) in both AN3CA and A2780 cells. The inhibition of the downstream protein p-PRAS40 (T246) is observed with ARQ-092 (IC50=0.31 uM)[1].
In a mouse pharmacokinetic study, (po at 100 mg/kg, iv at 5 mg/kg), ARQ-092 (Compound 21a) shows an oral bioavailability of 23%. ARQ-092 results in 99%, 95% and 58% reductions in p-Akt (S473), p-Akt (T306) and p-PRAS40 (T246), respectively, after tumor-bearing mice are treated with 100 mg/kg po. The inhibition of phosphorylation is sustained at eight hours.The plasma concentration of ARQ-092 at one hour is 2.1 uM and decreased to 0.26 uM at 8 hours, while in the tumor, the concentration is 21.0 uM at one hour and 9.6 uM at 8 hours[1]. To determine the effects of ARQ-092 on cardiac function, echocardiographic analysis of SHP2+/+ and SHP2Y279C/+ littermates is conducted, either in the presence of orally administered vehicle or ARQ-092 (100 mg/kg/day), at 12, 14, and 16 weeks of age. By 12 weeks of age, SHP2Y279C/+ mice show significant left ventricular hypertrophy, as indicated by decreased chamber dimension and increased posterior wall thickness compared with those of littermate controls; hypertrophy in these mice continued to progress over the 4 week time period. Treatment of the SHP2Y279C/+ mice with ARQ-092 normalizes the hypertrophic cardiomyopathy (HCM) phenotype as early as 2 weeks following treatment, with levels comparable to those in SHP2+/+ at this time point[2].
References:
[1]. Lapierre JM, et al. Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor. J Med Chem. 2016 Jul 14;59(13):6455-69.
[2]. Wang J, et al. In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy. PLoS One. 2017 Jun 5;12(6):e0178905.
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Cell experiment: |
Anti-proliferative cellular assays are conducted using the CellTiter Non-Radioactive Cell Proliferation Assay, which utilizes the production of formazan from a tetrazolium compound by live cells. AN3CA and A2780 cells are obtained from the ATCC. AN3CA cells are cultured in DMEM, and A2780 cells are cultured in RPMI. Cells are plated in 96-well plates at 2,000-10,000 cells/well, cultured for 24 h, and treated with the test compound for 72 h at a final DMSO concentration no greater than 0.5% v/v. PMS stock reagent (0.92 mg/mL in DPBS) is diluted 20-fold in MTS stock reagent (2 mg/mL in DPBS), and this MTS/PMS mixture is diluted 5-fold into each well of the 96-well plate. The plates are incubated for 3-4 h, and the absorbance of formazan is measured at 490 nm. The data are normalized to the untreated controls, the dose-response curves are fit to a four-parameter logistic equation, and the IC50 values are determined. All IC50 values reported are the geometric mean of at least two independent determinations[1]. |
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Animal experiment: |
Mice[2] SHP2Y279C/+ mice are used. Only male progeny are used for the experiments herein and all mice are maintained on outbred C57BL6/J backgrounds, backcrossed for more than 10 generations. Either vehicle or Miransertib (100 mg/kg body weight) is then daily administered by oral gavage for 4 weeks. Administration began at 12 weeks of age (after established hypertrophy is indicated), and continued for 4 weeks, until the mice reach 16 weeks of age. As controls, SHP2+/+ and SHP2Y279C/+ mice are treated with vehicle alone. |
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References: [1]. Lapierre JM, et al. Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor. J Med Chem. 2016 Jul 14;59(13):6455-69. |
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| Cas No. | 1313881-70-7 | SDF | |
| 别名 | Miransertib | ||
| Canonical SMILES | NC1=NC=CC=C1C2=NC3=CC=C(C4=CC=CC=C4)N=C3N2C5=CC=C(C6(N)CCC6)C=C5 | ||
| 分子式 | C27H24N6 | 分子量 | 432.52 |
| 溶解度 | DMSO : ≥ 40.2 mg/mL (92.94 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.312 mL | 11.5602 mL | 23.1203 mL |
| 5 mM | 0.4624 mL | 2.312 mL | 4.6241 mL |
| 10 mM | 0.2312 mL | 1.156 mL | 2.312 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet