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Miransertib

Cat. No. M8909
Miransertib Structure
Synonym:

ARQ 092

Size Price Availability Quantity
10mg USD 280 In stock
50mg USD 1050 In stock
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Quality Control
  • Current batch:
  • Purity >98%
  • COA
  • MSDS
Biological Activity

Miransertib(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.

In vitro: ARQ-092 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.

In vivo: ARQ-092 (po at 100 mg/kg, iv at 5 mg/kg) in a mouse pharmacokinetic study 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 μM and decreased to 0.26 μM at 8 hours, while in the tumor, the concentration is 21.0 μM at one hour and 9.6 μM at 8 hours. 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.

Protocol
Cell Experiment
Cell lines AN3CA and A2780 cells
Preparation method AN3CA and A2780 cells are obtained from the ATCC. AN3CA cells are cultured in DMEM, and A2780 cells are cultured in RPMI supplemented with 10% FBS, 100 units/mL Penicillin, 100 μg/mL Streptomycin, and 2 mM Glutamine at 37 °C under 5% CO2. 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.
Concentrations final DMSO concentration no greater than 0.5% v/v
Incubation time 72 h
Animal Experiment
Animal models SHP2Y279C/+ mice
Formulation dissolved in 0.01 M phosphoric acid (vehicle) at a concentration of 20 mg/mL and filter sterilized
Dosages 100 mg/kg body weight
Administration oral gavage
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 432.52
Formula C27H24N6
CAS Number 1313881-70-7
Purity >98%
Solubility DMSO: ≥ 35 mg/mL
Storage at -20°C
References

In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy.
Wang J, et al. PLoS One. 2017 Jun 5;12(6):e0178905. PMID: 28582432.

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.
Lapierre JM, et al. J Med Chem. 2016 Jul 14;59(13):6455-69. PMID: 27305487.

Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome.
Lindhurst MJ, et al. Sci Rep. 2015 Dec 11;5:17162. PMID: 26657992.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: Miransertib, ARQ 092 supplier, Akt, inhibitors

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