AT7867 857531-00-1

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Molecular Weight: 337.85 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, respectively; little activity outside the AGC kinase family.


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 μM, 2.26 μM, 1.86 μM, 1.76 μM and 3.04 μM, respectively. AT7867
also suppresses the cell growth of U87MG, PC-3 and DU145 cells with IC50
of 8.22 μM, 10.37 μM and 11.86 μM, respectively.


AT7867 suppresses Akt
activity by inhibiting phosphorylation of GSK-3β in human tumor cells
with IC50 of 2-4 μM. 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.


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.

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 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 bovine serum albumin, and 30 μM ATP (1.16 Ci/mmol) for 4 hours. For PKA, the PKA enzyme and 50 μMpeptide (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 μMpeptide 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 bovine serum albumin, 0.001% Brij-35, 0.5% glycerol, and 15 μM ATP (2.3 Ci/mmol) for 60 min. For CDK2, the CDK2/cyclin A 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 bovine serum albumin, 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 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.

Cell Assay: [1]

Cell lines	MES-SA, MDA-MB-468, MCF-7, HCT116, HT29, U87MG, PC-3 and DU145 cells
Concentrations	0-100 μM , dissolved to a 10 mM stock in DMSO
Incubation Time	72 hours
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.

Animal Study: [1]

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.
Formulation	Formulated in a vehicle containing 10% DMSO, 20% water, and 70% hydroxypropyl-β-cyclodextrin (25% aqueous, w/v)
Dosages	20 mg/kg (i.p.) or 90 mg/kg (p.o.) once every 3 days
Administration	Administered via i.p. or p.o.
Solubility	15% Captisol, pH 9, 10 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Chemical Information

Molecular Weight (MW)	337.85
Formula	C20H20ClN3
CAS No.	857531-00-1

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	68 mg/mL (201.27 mM)
		Water	<1 mg/mL (
		Ethanol	5 mg/mL (14.79 mM)
	In vivo	15% Captisol, pH 9	10 mg/mL
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Name	4-(4-(1H-pyrazol-4-yl)phenyl)-4-(4-chlorophenyl)piperidine

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