Miransertib

Modify Date: 2024-01-02 22:23:42

Miransertib Structure
Miransertib structure
 Common Name Miransertib
CAS Number 1313881-70-7 Molecular Weight 432.520
Density 1.4±0.1 g/cm3 Boiling Point 700.8±70.0 °C at 760 mmHg
Molecular Formula C27H24N6 Melting Point N/A
MSDS N/A Flash Point 377.6±35.7 °C

 Use of 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.

 Names

Name 3-{3-[4-(1-Aminocyclobutyl)phenyl]-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl}-2-pyridinamine
Synonym More Synonyms

 Miransertib Biological Activity

Description 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.
Related Catalog
Target

Akt1:2.7 nM (IC50)

Akt3:8.1 nM (IC50)

Akt2:14 nM (IC50)

In Vitro 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 μM)[1].
In Vivo 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 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[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].
Cell Assay 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 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[1].
Animal Admin 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 ARQ-092 (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.
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.

 Chemical & Physical Properties

Density 1.4±0.1 g/cm3
Boiling Point 700.8±70.0 °C at 760 mmHg
Molecular Formula C27H24N6
Molecular Weight 432.520
Flash Point 377.6±35.7 °C
Exact Mass 432.206238
LogP 6.09
Vapour Pressure 0.0±2.2 mmHg at 25°C
Index of Refraction 1.742

 Synonyms

3-{3-[4-(1-Aminocyclobutyl)phényl]-5-phényl-3H-imidazo[4,5-b]pyridin-2-yl}-2-pyridinamine
2-Pyridinamine, 3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl]-
3-{3-[4-(1-Aminocyclobutyl)phenyl]-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl}-2-pyridinamin
3-{3-[4-(1-Aminocyclobutyl)phenyl]-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl}-2-pyridinamine
ARQ-092
AKT inhibitor 2
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Related Compounds: More...
Miransertib HCl
1313883-00-9
Chemsrc provides Miransertib(CAS#:1313881-70-7) MSDS, density, melting point, boiling point, structure, formula, molecular weight etc. Articles of Miransertib are included as well.>> amp version: Miransertib

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