AT7867 857531-00-1

.cp_wz tabla {borde superior: 1px sólido #ccc; borde izquierdo: 1px sólido #ccc; } .cp_wz table td {borde derecho: 1px sólido #ccc; borde inferior: 1px sólido #ccc; padding: 5px 0px 0px 5px;} .cp_wz table th {border-right: 1px solid #ccc; border-bottom: 1px solid #ccc; relleno: 5px 0px 0px 5px;} \ n Peso molecular: 337.85 AT7867 es un potente inhibidor competitivo de ATP de Akt1 / 2/3 y p70S6K / PKA con IC50 de 32 nM / 17 nM / 47 nM y 85 nM / 20 nM, respectivamente; poca actividad fuera de la familia de las quinasas AGC. \ n AT7867 también inhibe las quinasas AGC p70S6K y PKA relacionadas estructuralmente con IC50 de 20 nM y 85 nM, respectivamente. AT7867 muestra actividad competitiva de ATP a Akt2 con Ki de 18 nM. AT7867 exhibe antiproliferación en líneas celulares con mutaciones PTEN o PIK3CA y muestra gran potencia para MES-SA, MDA-MB-468, MCF-7, HCT116 y HT29 con IC50 de 0.94 μM, 2.26 μM, 1.86 μM, 1.76 μM y 3.04 μM , respectivamente. AT7867 también suprime el crecimiento celular de las células U87MG, PC-3 y DU145 con IC50 de 8,22 μM, 10,37 μM y 11,86 μM, respectivamente. AT7867 suprime la actividad de Akt al inhibir la fosforilación de GSK-3β en células tumorales humanas con IC50 de 2-4 μM. AT7867 también induce la fosforilación de los siguientes sustratos directos de Akt, incluidos los factores de transcripción proapoptóticos FKHR (FoxO1a), FKHRL1 (FoxO3a) y la diana S6RP aguas abajo en células U87MG. AT7867 muestra una biodisponibilidad del 44% en ratones por vía po. AT7867 podría aumentar la PARP escindida en xenoinjertos de MES-SA a 20 mg / kg ip o 90 mg / kg po. AT7867 inhibe significativamente el crecimiento tumoral en xenoinjertos MES-SA o xenoinjertos U87MG con T / C de 0,37 y 0,51, respectivamente.
orte

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.

Ensayo celular: [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.

Estudio con animales: [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.

Conversión de diferentes modelos de animales basados ​​en BSA (valor basado en datos del Borrador de Directrices de la FDA)

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

Por ejemplo, para modificar la dosis de resveratrol utilizada para un ratón (22,4 mg / kg) a una dosis basada en el BSA para una rata, multiplique 22,4 mg / kg por el factor Km para un ratón y luego divida por el factor Km para una rata. Este cálculo da como resultado una dosis equivalente para ratas de resveratrol de 11,2 mg / kg.

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

\ n Información química

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

Calculadora de molaridad Calculadora de dilución Calculadora de peso molecular

Grupos de Producto : PI3K / Akt / mTOR > Inhibidor de Akt