Chine GZD824 Dimésylate 1421783-64-3 Fabricants

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GZD824 Dimésylate 1421783-64-3

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 :
724,77 GZD824 Dimesylate est un nouvel inhibiteur de Bcr-Abl biodisponible par voie orale pour Bcr-Abl(WT) et Bcr-Abl(T315I) avec une IC50 de 0,34 nM et 0,68 nM, respectivement.
Activité biologique GZD824 inhibe puissamment la croissance des cellules Ba/F3 exprimant Bcr-Abl de type sauvage avec une CI50 de 1,0 nM. Très cohérent avec l'inhibition de la kinase biochimique et l'affinité de liaison étroite avec les protéines, le GZD824 inhibe également fortement la prolifération des cellules Ba/F3 exprimant le mutant Bcr-AblT315I et 14 autres mutants Bcr-Abl pertinents pour la résistance. De plus, GZD824 supprime efficacement l'activation de Bcr-Abl ainsi que Crkl et STAT5 en aval d'une manière dépendante de la concentration dans les cellules K562 CML. Le GZD824, à des doses de 5 et 10 mg/kg/jour, inhibe de manière dose-dépendante la croissance tumorale dans le modèle de xénogreffe tumorale K562 et le modèle de xénogreffe Ku812 sans mortalité ni perte corporelle significative. En outre, GZD824 (20 mg/kg/jour) supprime la croissance tumorale chez les souris portant des cellules Ba/F3 allogreffées exprimant Bcr-AblWT et Bcr-AblT315I. Protocole (uniquement pour référence) Dosage de la kinase : [1]

FRET-Based Z′-Lyte Assay Detecting Peptide Substrate Phosphorylation	The kinases ABL1, ABL1(E255K), ABL1 (G250E), ABL1(T315I), and ABL1(Y253F) are P3049, PV3864, PV3865, PV3866, and PV3863 are full-length human recombinant protein expressed in insect cells and histidine-tagged. Inhibition activities of inhibitors against Abl1 and its mutants are performed in 384-well plates using the FRET-based Z′-Lyte assay system. Briefly, the kinase substrate is diluted into 5 μL of kinase reaction buffer; and the kinase is added. Compounds (10 nL) with indicated concentrations are then delivered to the reaction by using Echo liquid handler, and the mixture is incubated for 30 min at room temperature. Then 5 μL of 2X ATP solution is added to initiate the reaction, and the mixture is further incubated for 2 h at room temperature. The resulting reactions contains 10 μM (for wild-type Abl1, and mutants Y253F, Q252H, M351T, and H396P) or 5 μM (for mutants E255K, G250E, T315I) of ATP, 2 μM of Tyr2 Peptide substrate in 50 mM HEPES (PH 7.5), 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA, 0.0247 μg/mL Abl1, and inhibitors as appropriate. Then, 5 μL of development reagent is added, and the mixture is incubated for 2 h at room temperature before 5 μL of stop solution is added. Fluorescence signal ratio of 445 nm (Coumarin)/520 nm (fluorescin) is examined on an EnVision Multilabel Reader. The data are analyzed using Graphpad Prism5. The data are the mean value of three experiments.

FRET-Based Z′-Lyte Assay Detecting Peptide Substrate Phosphorylation

The kinases ABL1, ABL1(E255K), ABL1 (G250E), ABL1(T315I), and ABL1(Y253F) are P3049, PV3864, PV3865, PV3866, and PV3863 are full-length human recombinant protein expressed in insect cells and histidine-tagged. Inhibition activities of inhibitors against Abl1 and its mutants are performed in 384-well plates using the FRET-based Z′-Lyte assay system. Briefly, the kinase substrate is diluted into 5 μL of kinase reaction buffer; and the kinase is added. Compounds (10 nL) with indicated concentrations are then delivered to the reaction by using Echo liquid handler, and the mixture is incubated for 30 min at room temperature. Then 5 μL of 2X ATP solution is added to initiate the reaction, and the mixture is further incubated for 2 h at room temperature. The resulting reactions contains 10 μM (for wild-type Abl1, and mutants Y253F, Q252H, M351T, and H396P) or 5 μM (for mutants E255K, G250E, T315I) of ATP, 2 μM of Tyr2 Peptide substrate in 50 mM HEPES (PH 7.5), 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA, 0.0247 μg/mL Abl1, and inhibitors as appropriate. Then, 5 μL of development reagent is added, and the mixture is incubated for 2 h at room temperature before 5 μL of stop solution is added. Fluorescence signal ratio of 445 nm (Coumarin)/520 nm (fluorescin) is examined on an EnVision Multilabel Reader. The data are analyzed using Graphpad Prism5. The data are the mean value of three experiments.

Dosage cellulaire : [1]

Cell lines	Ba/F3 cells expressing wildtype and mutant Bcr-Abl
Concentrations	0-50 μM
Incubation Time	72 hours
Method	Cells in the logarithmic phase are plated in 96-well culture dishes. Twenty-four hours later, cells are treated with the corresponding compounds or vehicle control at the indicated concentration for 72 h. CCK-8 is added into the 96-well plates (10 μL/well) and incubated with the cells for 3 h. OD450 and OD650 are determined by a microplate reader. Absorbance rate (A) for each well is calculated as OD450 – OD650. The cell viability rate for each well is calculated as V% = (As – Ac)/(Ab – Ac) × 100%, and the data were further analyzed using Graphpad Prism5. The data are the mean value of the three experiments. As is the absorbance rate of the test compound well, Ac is the absorbance rate of the well without either cell or test compound, and Ab is the absorbance rate of the well with cell and vehicle control.

Étude animale : [1]

Animal Models	Mice xenograft or allograft tumor models using K562 and transformed Ba/F3 cells expressing native Bcr-Abl or Bcr-Abl mutants.
Formulation	1% DMSO, 22.5% Cremophor, 7.5% ethanol, and 69% normal saline
Dosages	~20 mg/kg
Administration	oral gavage
Solubility	Saline, 20 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)	724.77
Formula	C29H27F3N6O.2CH4O3S
CAS No.	1421783-64-3

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

Solubility (25°C) *	In vitro	DMSO	100 mg/mL (137.97 mM)
		Water	100 mg/mL (137.97 mM)
		Ethanol	<1 mg/mL (
	In vivo	Saline	20 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	Benzamide, 4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]-, methanesulfonate (1:2)

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Groupes de Produits : L'angiogenèse > Inhibiteur Bcr-Abl