Chine AST-1306 1050500-29-2 Fabricants

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AST-1306 1050500-29-2

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 :
621.08 AST-1306 est un nouvel inhibiteur irréversible de l'EGFR et de l'ErbB2 avec une IC50 de 0,5 nM et 3 nM, également efficace dans la mutation EGFR T790M/L858R, plus puissant contre ErbB2 -cellules surexprimées, 3000 fois sélectives pour la famille ErbB par rapport aux autres kinases,
Activité biologique AST-1306 également ErB2 et EGFR T790M/L858R double mutant. L'AST-1306 est environ 500 fois plus puissant que le lapatinib et plus de 3000 fois sélectif pour les kinases de la famille ErbB par rapport aux autres familles de kinases, notamment PDGFR, KDR et c-Met. AST-1306 pourrait se lier de manière covalente à des résidus d'acides aminés spécifiques d'EGFR et d'ErbB2. AST-1306 agit d'une manière dépendante de la concentration pour inhiber de manière significative la croissance des cellules HIH3T3-EGFR T790M/L858R. AST-1306 supprime efficacement la phosphorylation de l'EGFR dans les cellules HIH3T3-EGFR T790M/L858R. De plus, AST-1306 bloque la croissance des cellules NCI-H1975 qui hébergent la mutation EGFR T790M/L858R d'une manière dépendante de la concentration. L'AST-1306 bloque également la phosphorylation de l'EGFR et des voies en aval. De plus, AST-1306 inhibe de manière dose-dépendante et marquée la phosphorylation de l'EGFR induite par l'EGF dans les cellules A549. L'AST-1306 inhibe la phosphorylation de l'EGFR et de l'ErbB2, et la signalisation en aval dans les cellules cancéreuses humaines, notamment les cellules A549, les cellules Calu-3 et les cellules SK-OV-3. L'administration orale deux fois par jour d'AST-1306 entraîne une prévention spectaculaire de la croissance tumorale dans les modèles de xénogreffe SK-OV-3 et Calu-3. Dans les modèles SK-OV-3, les tumeurs disparaissent presque après un traitement avec AST-1306 pendant 7 jours. En revanche, AST-1306 n'inhibe que légèrement la croissance de la tumeur dans les modèles de xénogreffe HO-8910 et A549. Par conséquent, l'efficacité antitumorale de l'AST-1306 est plus grande dans les modèles de tumeurs surexprimant ErbB2 que dans les modèles exprimant de faibles niveaux d'ErbB2. AST-1306 est bien toléré. Le lapatinib présente une activité antitumorale dans ces modèles tumoraux surexprimant ErbB2, mais l'AST-1306 est plus efficace que le lapatinib dans le modèle tumoral de xénogreffe SK-OV-3 lorsqu'il est administré à la même dose et au même schéma. De plus, l'administration orale d'AST-1306 deux fois par jour pendant 3 semaines supprime considérablement la croissance de la tumeur dans les modèles FVB-2/Nneu. Après un traitement de 11 jours, les tumeurs disparaissent presque complètement. Le poids corporel des souris diminue de moins de 20 % pendant le traitement. Protocole (uniquement pour référence) Dosage de la kinase : [1]

Tyrosine kinase assays	The tyrosine kinase activities are determined in 96-well ELISA plates precoated with 20 μg/mL Poly (Glu,Tyr)4:1. First, 80 μL of 5 μM ATP solution diluted in kinase reaction buffer (50 mM HEPES pH 7.4, 20 mM MgCl2, 0.1 mM MnCl2, 0.2 mM Na3VO4, 1 mM DTT) is added to each well. Various concentrations of AST-1306 diluted in 10 μL of 1% DMSO (v/v) are then added to each reaction well, with 1% DMSO (v/v) used as the negative control. Subsequently, the kinase reaction is initiated by the addition of purified tyrosine kinase proteins diluted in 10 μL of kinase reaction buffer solution. Experiments at each concentration are performed in duplicate. After incubation for 60 min at 37 °C, the plate is washed three times with phosphate buffered saline (PBS) containing 0.1% Tween 20 (T-PBS). Next, 100 μL anti-phosphotyrosine antibody (PY99, 1:500 dilution) diluted in T-PBS containing 5 mg/mL BSA is added. After 30 min incubation at 37 °C, the plate is washed three times as before. Horseradish peroxidase-conjugated goat anti-mouse IgG (100 μL) diluted 1:2000 in T-PBS containing 5 mg/mL BSA is added. The plate is reincubated at 37 °C for 30 min, and then washed with PBS. Finally, 100 μL of a solution containing 0.03 % H2O2 and 2 mg/mL o-phenylenediamine in 0.1 M citrate buffer, pH 5.5, is added and samples are incubated at room temperature until color emerged. The reaction is terminated by the addition of 50 μL of 2 M H2SO4, and the plate is read using a multi-well spectrophotometer at 490 nm. The inhibition rate (%) is calculated using the following equation: [1-(A490 treated /A490 control)] ×100%. IC50 values are determined from the results of at least three independent tests and calculated by Logit method.

Tyrosine kinase assays

The tyrosine kinase activities are determined in 96-well ELISA plates precoated with 20 μg/mL Poly (Glu,Tyr)4:1. First, 80 μL of 5 μM ATP solution diluted in kinase reaction buffer (50 mM HEPES pH 7.4, 20 mM MgCl2, 0.1 mM MnCl2, 0.2 mM Na3VO4, 1 mM DTT) is added to each well. Various concentrations of AST-1306 diluted in 10 μL of 1% DMSO (v/v) are then added to each reaction well, with 1% DMSO (v/v) used as the negative control. Subsequently, the kinase reaction is initiated by the addition of purified tyrosine kinase proteins diluted in 10 μL of kinase reaction buffer solution. Experiments at each concentration are performed in duplicate. After incubation for 60 min at 37 °C, the plate is washed three times with phosphate buffered saline (PBS) containing 0.1% Tween 20 (T-PBS). Next, 100 μL anti-phosphotyrosine antibody (PY99, 1:500 dilution) diluted in T-PBS containing 5 mg/mL BSA is added. After 30 min incubation at 37 °C, the plate is washed three times as before. Horseradish peroxidase-conjugated goat anti-mouse IgG (100 μL) diluted 1:2000 in T-PBS containing 5 mg/mL BSA is added. The plate is reincubated at 37 °C for 30 min, and then washed with PBS. Finally, 100 μL of a solution containing 0.03 % H2O2 and 2 mg/mL o-phenylenediamine in 0.1 M citrate buffer, pH 5.5, is added and samples are incubated at room temperature until color emerged. The reaction is terminated by the addition of 50 μL of 2 M H2SO4, and the plate is read using a multi-well spectrophotometer at 490 nm. The inhibition rate (%) is calculated using the following equation: [1-(A490 treated /A490 control)] ×100%. IC50 values are determined from the results of at least three independent tests and calculated by Logit method.

Dosage cellulaire : [1]

Cell lines	Calu-3 and A-549 cell lines
Concentrations	0.001-1 μM
Incubation Time	72 hours
Method	Cell (including Calu-3, A-549 cell line et al.) proliferation is evaluated using the SRB (Sulforhodamine B) assay. Briefly, cells are seeded into 96-well plates and grown for 24 hours. The cells are then treated with increasing concentrations of AST-1306 and grown for a further 72 hours. The medium remains unchanged until the completion of the experiment. The cells are then fixed with 10% precooled trichloroacetic acid (TCA) for 1 hour at 4 °C and stained for 15 min at room temperature with 100 μL of 4 mg/mL SRB solution in 1% acetic acid. The SRB is then removed, and the cells are quickly rinsed five times with 1% acetic acid. After cells are air-dried, protein-bound dye is dissolved in 150 μL of 10 mM Tris base for 5 min and measured at 515 nm using a multiwell spectrophotometer. The inhibition rate on cell proliferation is calculated as (1 - A515 treated/A515 control) × 100%. The IC50 value is obtained by the Logit method and is determined from the results of at least 3 independent tests.

Étude animale : [1]

Animal Models	Nude mice bearing SK-OV-3 xenograft tumors and SK-OV-3FVB-2/Nneu transgenic mouse
Formulation	0.5% hydroxypropyl methylcellulose (HPMC), grinding with agate morta
Dosages	25 mg/kg, 50 mg/kg and 100 mg/kg
Administration	p.o., twice daily
Solubility	0.5% hydroxyethyl cellulose, 30 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)	621.08
Formula	C24H18ClFN4O2,C7H8O3S
CAS No.	1050500-29-2

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

Solubility (25°C) *	In vitro	DMSO	124 mg/mL (199.65 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	In vivo	0.5% hydroxyethyl cellulose	30 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.