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AT7867 dihydrochloride

Akt1 and p70S6K/PKA inhibitor CAS# 1431697-86-7

AT7867 dihydrochloride

Catalog No. BCC1378----Order now to get a substantial discount!

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Quality Control of AT7867 dihydrochloride

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Chemical structure

AT7867 dihydrochloride

3D structure

Chemical Properties of AT7867 dihydrochloride

Cas No. 1431697-86-7 SDF Download SDF
PubChem ID 71576653 Appearance Powder
Formula C20H22Cl3N3 M.Wt 410.77
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 50 mg/mL (121.72 mM; Need ultrasonic)
Chemical Name 4-(4-chlorophenyl)-4-[4-(1H-pyrazol-4-yl)phenyl]piperidine;dihydrochloride
SMILES C1CNCCC1(C2=CC=C(C=C2)C3=CNN=C3)C4=CC=C(C=C4)Cl.Cl.Cl
Standard InChIKey ICUAUJBVBVIUAE-UHFFFAOYSA-N
Standard InChI InChI=1S/C20H20ClN3.2ClH/c21-19-7-5-18(6-8-19)20(9-11-22-12-10-20)17-3-1-15(2-4-17)16-13-23-24-14-16;;/h1-8,13-14,22H,9-12H2,(H,23,24);2*1H
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 AT7867 dihydrochloride

DescriptionAT7867 dihydrochloride is a potent ATP-competitive inhibitor of Akt1/Akt2/Akt3 and p70S6K/PKA with IC50s of 32 nM/17 nM/47 nM and 85 nM/20 nM, respectively.In Vitro:The inhibition of AKT2 by AT7867 is shown to be ATP-competitive with a Ki of 18nM. AT7867 also displays potent activity against the structurally related AGC kinases p70S6K and PKA, but shows a clear window of selectivity against kinases from other kinase sub-families. In vitro growth inhibition studies show that AT7867 blocks proliferation in a number of human cancer cell lines. AT7867 appears to be most potent at inhibiting proliferation in MES-SA uterine, MDA-MB-468 and MCF-7 breast, and HCT116 and HT29 colon lines (IC50 values range from 0.9-3 μM), and least effective in the two prostate lines tested (IC50 values range from 10-12 μM) [1].In Vivo:Following oral administration at 20 mg/kg, the elimination of AT7867 from plasma appears to be similar to that observed after i.v. administration. Plasma levels of AT7867 remain above 0.5 μM for at least 6 hours following an oral dose of 20 mg/kg. Assuming linear pharmacokinetics following i.v. administration, the bioavailability by the oral route is calculated to be 44%. In vivo pharmacodynamic (PD) biomarker studies are therefore performed with this model. Following pharmacokinetic and tolerability studies, doses of AT7867 (90 mg/kg p.o. or 20 mg/kg i.p.) are administered to athymic mice bearing MES-SA tumors and the phosphorylation status of GSK3β and S6RP in tumors is monitored over time. Clear inhibition of phosphorylation of the two markers of pathway activity is seen at 2 and 6 hours following treatment with AT7867. By 24 hours, total levels of both GSK3β and S6RP are greatly reduced[1].

References:
[1]. Grimshaw KM, et al. AT7867 is a potent and oral inhibitor of AKT and p70 S6 kinase that induces pharmacodynamic changes and inhibits human tumor xenograft growth. Mol Cancer Ther, 2010, 9(5), 1100-1110.

Protocol

Kinase Assay [1]
Kinase assays for AKT2, PKA, p70S6K and CDK2/cyclinA are all carried out in a radiometric filter binding format. Assay reactions are set up in the presence of compound. For AKT2, the AKT2 enzyme and 25 μM AKTide-2T peptide (HARKRERTYSFGHHA) are incubated in 20 mM MOPS, pH 7.2, 25 mM β-glycerophosphate, 5 mM EDTA, 15 mM MgCl2, 1 mM sodium orthovanadate, 1 mM DTT, 10 μg/mL BSA and 30 μM ATP (1.16 Ci/mmol) for 4 hours. For PKA, the PKA enzyme and 50 μM peptide (GRTGRRNSI) are incubated in 2 mM MOPS, pH 7.2, 25 mM β-glycerophosphate, 5 mM EDTA, 15 mM MgCl2, 1 mM orthovanadate, 1 mM DTT and 40 μM ATP (0.88 Ci/mmol) for 20 minutes. For p70S6K, the p70S6K enzyme and 25 μM peptide substrate (AKRRRLSSLRA) are incubated in 10 mM MOPS, pH 7, 0.2 mM EDTA, 1 mM MgCl2, 0.01% β-mercaptoethanol, 0.1 mg/mL BSA, 0.001% Brij-35, 0.5% glycerol and 15μM ATP (2.3 Ci/mmol) for 60 minutes. For CDK2, the CDK2/cyclinA enzyme and 0.12 μg/ml Histone H1 are incubated in 20 mM MOPS, pH 7.2, 25 mM β-glycerophosphate, 5 mM EDTA, 15 mM MgCl2, 1 mM sodium orthovanadate, 1 mM DTT, 0.1 mg/ml BSA and 45 μM ATP (0.78 Ci/mmol) for 4 hours. Assay reactions are stopped by adding an excess of orthophosphoric acid and the stopped reaction mixture is then transferred to Millipore MAPH filter plates and filtered. The plates are then washed, scintillant added and radioactivity measured by scintillation counting on a Packard TopCount. IC50 values are calculated from replicate curves using GraphPad Prism software. AKT1 and 3 enzyme assays are carried out, while all other enzyme assays are performed[1].

Cell Assay [1]
Cells are plated in 96-well microplates at 16,000 cells per well in medium supplemented with 10% FBS, and grown for 24 hours before treatment with AT7867. AT7867 or vehicle control are added to the cells for 1 hour. Following this, cells are fixed with 3% paraformaldehyde, 0.25% glutaraldehyde, 0.25% Triton-X100, washed and blocked with 5% milk in tris-buffered saline with 0.1% Tween-20 (TBST) prior to overnight incubation with a phospho-GSK3β (serine 9) antibody. The plates are then washed, secondary antibody added, and enhancement of the signal performed using DELFIA reagents. Europium counts are normalized to the protein concentration, and the IC50 value for each inhibitor is calculated in GraphPad Prism using non-linear regression analysis and a sigmoidal dose-response (variable slope) equation[1].

Animal Administration [1]
Mice[1] Male athymic BALB/c mice (nu/nu) are used. A single dose of AT7867 is administered to BALB/c mice at 5 mg/kg intravenously (i.v.) and 20 mg/kg per os (p.o.). Plasma samples are collected from duplicate animals at each of the following time points; 0.083, 0.167, 0.33, 0.67, 1, 2, 4, 6, 16 and 24 hours following i.v. dosing and at 0.25, 0.5, 1, 2, 4, 6 and 24 hours following p.o. dosing. Mice are bled by cardiac puncture and all blood samples are centrifuged to obtain plasma, which is then frozen at -20°C until analysis. For bioanalysis, all plasma samples are prepared by protein precipitation with acetonitrile containing internal standard. Quantification of sample extracts is by comparison with a standard calibration line constructed with AT7867 and using an inhibitor specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters are determined.

References:
[1]. Grimshaw KM, et al. AT7867 is a potent and oral inhibitor of AKT and p70 S6 kinase that induces pharmacodynamic changes and inhibits human tumor xenograft growth. Mol Cancer Ther, 2010, 9(5), 1100-1110.

AT7867 dihydrochloride Dilution Calculator

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AT7867 dihydrochloride Molarity Calculator

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Preparing Stock Solutions of AT7867 dihydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.4345 mL 12.1723 mL 24.3445 mL 48.689 mL 60.8613 mL
5 mM 0.4869 mL 2.4345 mL 4.8689 mL 9.7378 mL 12.1723 mL
10 mM 0.2434 mL 1.2172 mL 2.4345 mL 4.8689 mL 6.0861 mL
50 mM 0.0487 mL 0.2434 mL 0.4869 mL 0.9738 mL 1.2172 mL
100 mM 0.0243 mL 0.1217 mL 0.2434 mL 0.4869 mL 0.6086 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 AT7867 dihydrochloride

IC50: AKT1 32 nM, AKT2 17 nM, AKT3 47 nM, PKA 20 nM
The serine/threonine kinase AKT plays a pivotal role in signal transduction events involved in malignant transformation and chemoresistance and is an attractive target for the development of cancer therapeutics. Structure-based drug design and fragment-based lead discovery have identified AT7867 as a novel and potent inhibitor of both AKT and the downstream kinase p70 S6 kinase (p70S6K) and also of protein kinase A.
In vitro: AT7867 potently inhibits both AKT and p70S6K activity, measured by inhibition of protein phosphorylation of GSK3β and S6 ribosomal, and also the growth inhibition in a panel of human cancer cell lines. Induction of apoptosis by AT7867 was detected by multiple methods in tumor cells followingAT7867 treatment [1].
In vivo: Administration ofAT7867 (90 mg/kg p.o. or 20 mg/kg i.p.) to athymic mice implanted with the PTEN-deficient U87MG human glioblastoma xenograft model caused inhibition of phosphorylation of downstream substrates of both AKTand p70S6K and induction of apoptosis. These AT7867 doses also led to inhibition of human tumor growth in PTEN-deficient xenograft models. These findings suggest that a novel strategy of AKT and p70S6K blockade may have therapeutic value and supports further evaluation of AT7867 as a singleagent anticancer strategy [1].
Clinical trial: Currently no clinical data are available.
References:
[1] Grimshaw KM, Hunter LJ, Yap TA, Heaton SP, Walton MI, Woodhead SJ, Fazal L, Reule M, Davies TG, Seavers LC, Lock V, Lyons JF, Thompson NT, Workman P, Garrett MD. AT7867 is a potent and oral inhibitor of AKT and p70 S6 kinase that induces pharmacodynamic changes and inhibits human tumor xenograft growth. Mol Cancer Ther. 2010;9(5):1100-10.

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Description

AT7867 dihydrochloride is a potent ATP-competitive inhibitor of Akt1/Akt2/Akt3 and p70S6K/PKA with IC50s of 32 nM/17 nM/47 nM and 85 nM/20 nM, respectively.

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