AT7867

ArtNr	S1558-50
Hersteller	Selleckchem
CAS-Nr.	857531-00-1
Menge	50 mg
Quantity options	10 mg 1 g 10 g 10 mM/1 ml 200 mg 50 mg 5 g
Kategorie	Oncology Neuroscience Metabolism Diabetes Aging & Neurological Disorders Inhibitors & Compound Libraries Small Molecules By Organ Brain Cancer
Typ	Inhibitors
Specific against	other
Smiles	C1CNCCC1(C2=CC=C(C=C2)C3=CNN=C3)C4=CC=C(C=C4)Cl
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	857531-00-1'
Similar products	AT7867
Lieferbar
Manufacturer - Targets	AKT3, AKT2, AKT1
Storage Conditions	2 years -80 in solvent
Molecular Weight	337, 85
Administration	Administered via i.p. or p.o.
Animal Models	Human MES-SA uterine sarcoma cells or U87MG human glioblastoma cells are injected s.c. in the right flank of BALB/c mice.
Cell lines	MES-SA, MDA-MB-468, MCF-7, HCT116, HT29, U87MG, PC-3 and DU145 cells
Concentrations	0-100 uM , dissolved to a 10 mM stock in DMSO
Dosages	20 mg/kg (i.p.) or 90 mg/kg (p.o.) once every 3 days
Formulation	Formulated in a vehicle containing 10% DMSO, 20% water, and 70% hydroxypropyl-beta-cyclodextrin (25% aqueous, w/v)
IC50	32 nM, 32 nM, 32 nM, 32 nM, 32 nM, 32 nM
In vitro	AT7867 also inhibits structurally related AGC kinases p70S6K and PKA with IC50 of 20 nM and 85 nM, respectively. AT7867 shows ATP-competitive activity to Akt2 with Ki of 18 nM. AT7867 exhibits antiproliferation in cell lines with PTEN or PIK3CA mutations and shows great potent to MES-SA, MDA-MB-468, MCF-7, HCT116 and HT29 with IC50 of 0.94 uM, 2.26 uM, 1.86 uM, 1.76 uM and 3.04 uM, respectively. AT7867 also suppresses the cell growth of U87MG, PC-3 and DU145 cells with IC50 of 8.22 uM, 10.37 uM and 11.86 uM, respectively. AT7867 suppresses Akt activity by inhibiting phosphorylation of GSK-3beta in human tumor cells with IC50 of 2-4 uM. AT7867 also induces the phosphorylation of the following Akt direct substrates including proapoptotic transcription factors FKHR (FoxO1a), FKHRL1 (FoxO3a) and the downstream target S6RP in U87MG cells. [1]
In vivo	AT7867 shows bioavailability of 44% in mice by p.o. route. AT7867 could increase the cleaved PARP in MES-SA xenografts at 20 mg/kg i.p. or 90 mg/kg p.o.. AT7867 significantly inhibits the tumor growth in MES-SA xenografts or U87MG xenografts with T/C of 0.37 and 0.51, respectively. [1]
Incubation Time	72 hours
Kinase Assay	In vitro kinase assays, Kinase assays for Akt2, PKA, p70S6K, and CDK2/cyclin A are all carried out in a radiometric filter binding format. Assay reactions are set up in the presence of AT7867. For Akt2, the Akt2 enzyme and 25 uM Aktide-2T peptide (HARKRERTYSFGHHA) are incubated in 20 mM MOPS (pH 7.2), 25 mM beta-glycerophosphate, 5 mM EDTA, 15 mM MgCl2, 1 mM sodium orthovanadate, 1 mM DTT, 10 ug/mL bovine serum albumin, and 30 uM ATP (1.16 Ci/mmol) for 4 hours. For PKA, the PKA enzyme and 50 uMpeptide (GRTGRRNSI) are incubated in 2 mM MOPS (pH 7.2), 25 mM beta-glycerophosphate, 5 mM EDTA, 15 mM MgCl2, 1 mM orthovanadate, 1 mM DTT, and 40 uM ATP (0.88 Ci/mmol) for 20 minutes. For p70S6K, the p70S6K enzyme and 25 uMpeptide substrate (AKRRRLSSLRA) are incubated in 10 mM MOPS (pH 7), 0.2 mM EDTA, 1 mM MgCl2, 0.01% beta-mercaptoethanol, 0.1 mg/mL bovine serum albumin, 0.001% Brij-35, 0.5% glycerol, and 15 uM ATP (2.3 Ci/mmol) for 60 min. For CDK2, the CDK2/cyclin A enzyme and 0.12 ug/mL histone H1 are incubated in 20 mM MOPS (pH 7.2), 25 mM beta-glycerophosphate, 5 mM EDTA, 15 mM MgCl2, 1 mM sodium orthovanadate, 1 mM DTT, 0.1 mg/mL bovine serum albumin, and 45 uM 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 is added, and radioactivity is measured by scintillation counting on a Packard TopCount. IC50 values are calculated from replicate curves using GraphPad Prism software. Akt1 and Akt3 enzyme assays are carried out.
Method	Cells are plated in 96-well microplates at 5, 103 per well in medium supplemented with 10% fetal bovine serum and grown for 24 hours before treatment with AT7867. AT7867 or vehicle control is added to the cells for 72 hours. Following this, Alamar Blue solution is added. The IC50 value for AT7868 is calculated in GraphPad Prism using nonlinear regression analysis and a sigmoidal dose-response (variable slope) equation.
Solubility (25C)	DMSO 68 mg/mL, Water <1 mg/mL, Ethanol 5 mg/mL
Information	AT7867 is a potent ATP-competitive inhibitor of Akt1/2/3 and p70S6K/PKA with IC50 of 32 nM/17 nM/47 nM and 85 nM/20 nM in cell-free assays, respectively; little activity outside the AGC kinase family.
Chemical Name	4-(4-(1H-pyrazol-4-yl)phenyl)-4-(4-chlorophenyl)piperidine

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