Chine AT7867 857531-00-1 Fabricants

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AT7867 857531-00-1

Informations de base

Description du produit .cp_wz table {border-top : 1px solide #ccc;border-left:1px solide #ccc ; } .cp_wz table td{border-right : 1px solide #ccc ; border-bottom : 1px solide #ccc ; remplissage : 5px 0px 0px 5px;} .cp_wz table th {border-right : 1px solid #ccc;border-bottom : 1px solid #ccc ; rembourrage : 5px 0px 0px 5px;}
Poids moléculaire : 337,85 AT7867 est un puissant inhibiteur compétitif de l'ATP d'Akt1/2/3 et p70S6K/PKA avec une IC50 de 32 nM/17 nM/47 nM et 85 nM/20 nM, respectivement; peu d'activité en dehors de la famille des kinases AGC.
AT7867 inhibe également les kinases AGC p70S6K et PKA structurellement apparentées avec une CI50 de 20 nM et 85 nM, respectivement. AT7867 montre une activité ATP compétitive par rapport à Akt2 avec un Ki de 18 nM. AT7867 présente une antiprolifération dans les lignées cellulaires avec des mutations PTEN ou PIK3CA et montre une grande puissance contre MES-SA, MDA-MB-468, MCF-7, HCT116 et HT29 avec une CI50 de 0,94 M, 2,26 M, 1,86 M, 1,76 M et 3,04 M , respectivement. AT7867 supprime également la croissance cellulaire des cellules U87MG, PC-3 et DU145 avec une CI50 de 8,22 M, 10,37 M et 11,86 M, respectivement. AT7867 supprime l'activité Akt en inhibant la phosphorylation de GSK-3β dans les cellules tumorales humaines avec une CI50 de 2-4 M. AT7867 induit également la phosphorylation des substrats directs Akt suivants, y compris les facteurs de transcription pro-apoptotiques FKHR (FoxO1a), FKHRL1 (FoxO3a) et la cible en aval S6RP dans les cellules U87MG. AT7867 montre une biodisponibilité de 44% chez la souris par voie po. AT7867 pourrait augmenter la PARP clivée dans les xénogreffes MES-SA à 20 mg/kg ip ou 90 mg/kg po. AT7867 inhibe significativement la croissance tumorale dans les xénogreffes MES-SA ou les xénogreffes U87MG avec un T/C de 0,37 et 0,51, respectivement.

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.

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.

Dosage cellulaire : [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.

Étude animale : [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 de différents animaux modèles sur la base de la BSA (valeur basée sur les données des lignes directrices provisoires 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

Par exemple, pour modifier la dose de resvératrol utilisée pour une souris (22,4 mg/kg) à une dose basée sur la BSA pour un rat, multiplier 22,4 mg/kg par le facteur Km pour une souris puis diviser par le facteur Km pour un rat. Ce calcul donne une dose équivalente chez le rat pour le resvératrol 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)

Informations chimiques

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

Storage	3 years -20℃Powder
Storage	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.