AT7867

Akt1/2/3 and p70S6K/PKA inhibitor CAS# 857531-00-1

AT7867

Catalog No. BCC2536----Order now to get a substantial discount!

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Chemical structure

AT7867

3D structure

Chemical Properties of AT7867

Cas No. 857531-00-1 SDF Download SDF
PubChem ID 11175137 Appearance Powder
Formula C20H20ClN3 M.Wt 337.85
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 10 mg/mL (29.60 mM; Need ultrasonic)
Chemical Name 4-(4-chlorophenyl)-4-[4-(1H-pyrazol-4-yl)phenyl]piperidine
SMILES C1CNCCC1(C2=CC=C(C=C2)C3=CNN=C3)C4=CC=C(C=C4)Cl
Standard InChIKey LZMOSYUFVYJEPY-UHFFFAOYSA-N
Standard InChI InChI=1S/C20H20ClN3/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)
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

DescriptionAT7867 is a potent ATP-competitive inhibitor of Akt1/2/3 and p70S6K/PKA with IC50 values of 32 nM/17 nM/47 nM and 85 nM/20 nM, respectively
TargetsAkt2PKAAkt1Akt3p70 S6K  
IC5017 nM20 nM32 nM47 nM85 nM  

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 Dilution Calculator

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AT7867 Molarity Calculator

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Preparing Stock Solutions of AT7867

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.9599 mL 14.7995 mL 29.5989 mL 59.1979 mL 73.9973 mL
5 mM 0.592 mL 2.9599 mL 5.9198 mL 11.8396 mL 14.7995 mL
10 mM 0.296 mL 1.4799 mL 2.9599 mL 5.9198 mL 7.3997 mL
50 mM 0.0592 mL 0.296 mL 0.592 mL 1.184 mL 1.4799 mL
100 mM 0.0296 mL 0.148 mL 0.296 mL 0.592 mL 0.74 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

AT7867 is a potent ATP-competitive inhibitor of Akt1/2/3 and p70S6K/PKA (IC50=32 nM/17 nM/47 nM and 85 nM/20 nM, respectively).

Akt, also known as protein kinase B, is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration.

AT7867 inhibited cell proliferation in multiple human cancer cell lines, it is most potent in inhibiting MES-SA uterine/MDA-MB-468/MCF-7 breast/HCT116/HT29 colon lines (IC50, 0.9–3 μM). AT7867 also inhibited GSK3β among each cell lines tested (IC50=2-4 μM). In U87MG human glioblastoma cells, AT7867 suppressed AKT signaling and induced apoptosis in a time and concentration-dependent manner. [1]

In athymic mice implanted with the PTEN-deficient U87MG human glioblastoma xenograft model, AT7867 treatment showed inhibition in phosphorylation of AKT/p70S6K downstream substrates and led to apoptosis. In PTEN-dificient xenograft models, AT7867 inhibited human tumor growth. [1]

Reference:
Grimshaw KM, Hunter LJ, Yap TA 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 May;9(5):1100-10.

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References on AT7867

AT7867 is a potent and oral inhibitor of AKT and p70 S6 kinase that induces pharmacodynamic changes and inhibits human tumor xenograft growth.[Pubmed:20423992]

Mol Cancer Ther. 2010 May;9(5):1100-10.

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. Fragment-based lead discovery, combined with structure-based drug design, has recently 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. This ATP-competitive small molecule potently inhibits both AKT and p70S6K activity at the cellular level, as measured by inhibition of GSK3beta and S6 ribosomal protein phosphorylation, and also causes growth inhibition in a range of human cancer cell lines as a single agent. Induction of apoptosis was detected by multiple methods in tumor cells following AT7867 treatment. Administration of AT7867 (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 AKT and p70S6K and induction of apoptosis, confirming the observations made in vitro. These doses of AT7867 also resulted in inhibition of human tumor growth in PTEN-deficient xenograft models. These data suggest that the novel strategy of AKT and p70S6K blockade may have therapeutic value and supports further evaluation of AT7867 as a single-agent anticancer strategy.

AT7867 Inhibits Human Colorectal Cancer Cells via AKT-Dependent and AKT-Independent Mechanisms.[Pubmed:28081222]

PLoS One. 2017 Jan 12;12(1):e0169585.

AKT is often hyper-activated in human colorectal cancers (CRC). This current study evaluated the potential anti-CRC activity by AT7867, a novel AKT and p70S6K1 (S6K1) dual inhibitor. We showed that AT7867 inhibited survival and proliferation of established (HT-29, HCT116 and DLD-1 lines) and primary human CRC cells. Meanwhile, it provoked caspase-dependent apoptosis in the CRC cells. Molecularly, AT7867 blocked AKT-S6K1 activation in CRC cells. Restoring AKT-S6K1 activation, via expression of a constitutively-active AKT1 ("ca-AKT1"), only partially attenuated AT7867-induced HT-29 cell death. Further studies demonstrated that AT7867 inhibited sphingosine kinase 1 (SphK1) activity to promote pro-apoptotic ceramide production in HT-29 cells. Such effects by AT7867 were independent of AKT inhibition. AT7867-indued ceramide production and subsequent HT-29 cell apoptosis were attenuated by co-treatment of sphingosine-1-phosphate (S1P), but were potentiated with the glucosylceramide synthase (GCS) inhibitor PDMP. In vivo, intraperitoneal injection of AT7867 inhibited HT-29 xenograft tumor growth in nude mice. AKT activation was also inhibited in AT7867-treated HT-29 tumors. Together, the preclinical results suggest that AT7867 inhibits CRC cells via AKT-dependent and -independent mechanisms.

Description

AT7867 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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