KW-2478 819812-04-9

.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: \ n 574.66 KW-2478 es un inhibidor de HSP90 no anamicina con IC50 de 3.8 nM. Fase 1. \ n Actividad biológica KW-2478 inhibe la unión de bRD a Hsp90α con IC50 de 3,8 nM. KW-2478 degrada las proteínas cliente Hsp90, incluidas FGFR3 e IGF-1Rβ y c-Raf-1. KW-2478 reduce el nivel de Erk1 / 2 fosforilado. KW-2478 induce la apoptosis por escisión de PARP, un sustrato de caspasa-3 en células U266. KW-2478 tiene una actividad antiproliferativa dependiente del tiempo, es necesaria la exposición consecutiva al fármaco durante al menos 12 horas para ejercer una potente actividad antitumoral. KW-2478 regula negativamente los productos de translocación del locus IgH. KW-2478 inhibe la transcripción de los genes c-Maf y ciclina D1 suprimiendo principalmente la función de Cdk9. KW-2478 tiene actividades inhibidoras del crecimiento potentes y amplias contra varias líneas celulares, KW-2478 inhibe el crecimiento de células cancerosas en todas las líneas celulares, con CE50 de 101-252 nM, 81,4-91,4 nM y 120-622 nM para linfoma de células B, linfoma de células del manto y mieloma múltiple, respectivamente. KW-2478 también muestra una potente actividad inhibidora del crecimiento en células CLL y NHL primarias con CE50 de 40-170 nM y 200-400 nM, respectivamente. KW-2478 suprime el crecimiento tumoral e induce la degradación de proteínas cliente en tumores en el modelo inoculado con NCI-H929 sc a dosis de 100 mg / kg o más. KW-2478 reduce tanto la proteína M sérica como la carga tumoral de MM en la médula ósea en el modelo de ratón inoculado con OPM-2 / GFP iv a dosis de 100 mg / kg. Protocolo (solo como referencia) Ensayo de quinasa: [1]

Hsp90 Binding Assay

Human Hsp90α solution (0.5 μg/mL) is fixed on 96-well plates, followed by blocking with TBS containing 1% bovine serum albumin. KW-2478 solutions is added to the wells, and bRD is added to a concentration of 0.1 μmol/L. After removal of solution, poly-HRP streptavidin solution dilutes with poly-HRP dilution buffer is added to the wells. After removal of solution, equal volumes of TMB peroxidase substrate and peroxidase solution B are added to the wells. To stop the HRP reaction, 2 mol/L H2SO4 are added, followed by measurement of absorbance at 450 nm using a microplate spectrophotometer.

Ensayo celular: [1]

Cell lines	Human Hsp90α solution (0.5 μg/mL) is fixed on 96-well plates, followed by blocking with TBS containing 1% bovine serum albumin. KW-2478 solutions is added to the wells, and bRD is added to a concentration of 0.1 μmol/L. After removal of solution, poly-HRP
Concentrations	0.05 - 5 μM
Incubation Time	3 days
Method	To measure the IC50, OPM-2/green fluorescent protein (GFP) cells, KMS-11 cells, OPM-2/GFP and other cells are plated into 96-well plates and treat with KW-2478. After 72 hours of cultivation, cell viability is determined using Cell Proliferation Reagent WST-1. WST reagent is added to the wells, followed by incubation for 4 hours at 37 °C. After that, the absorbance at 450 nm with reference at 650 nm is measured with a microplate spectrophotometer. To examine time dependency of antiproliferative activity of KW-2478, the cells are plated into 96-well V-bottomed plates and treated with KW-2478. After 0 hour and at intervals from 3 to 72 hours at 37 °C, the supernatant is aspirated. After drug-free medium is added to the wells, the supernatant is aspirated again. Finally, drug-free medium is added to the wells, and the plates are further incubated for the remainder of the 72-hour period, followed by measurement of cell viabil

Estudio con animales: [1]

Animal Models	NCI-H929 tumors s.c. inoculated in SCID mice, OPM-2/GFP i.v. inoculated mouse model
Formulation	sterile 0.9% sodium chloride solution
Dosages	25, 50 , 100 and 200 mg/kg
Administration	Orally administrated once daily for 5 days
Solubility	30% propylene glycol, 5% Tween 80, 65% D5W, 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)

Información química

Molecular Weight (MW)	574.66
Formula	C30H42N2O9
CAS No.	819812-04-9

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

Solubility (25°C) *	In vitro	DMSO	115 mg/mL (200.11 mM)
		Water	<1 mg/mL (
		Ethanol	3 mg/mL (5.22 mM)
	In vivo	30% propylene glycol, 5% Tween 80, 65% D5W	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	2-(2-ethyl-3,5-dihydroxy-6-(3-methoxy-4-(2-morpholinoethoxy)benzoyl)phenyl)-N,N-bis(2-methoxyethyl)acetamide

Calculadora de molaridad Calculadora de dilución Calculadora de peso molecular

Grupos de Producto : Señalización citoesquelética > Inhibidor de HSP