BIIB021 848695-25-0

.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; padding: 5px 0px 0px 5px;} \ n Peso molecular: \ n 318.76 BIIB021 es un inhibidor de molécula pequeña completamente sintético disponible por vía oral de HSP90 con Ki y EC50 de 1.7 nM y 38 nM, respectivamente. Fase 2. \ n Actividad biológica BIIB021 se une en el bolsillo de unión de ATP de Hsp90, interfiere con la función de chaperona de Hsp90 y da como resultado la degradación de la proteína del cliente y la inhibición del crecimiento tumoral. BIIB021 inhibe la proliferación de células tumorales (BT474, MCF-7, N87, HT29, H1650, H1299, H69 y H82) con IC50 de 0.06-0.31 μM. BIIB021 induce la degradación de las proteínas cliente Hsp90, incluidas HER-2, Akt y Raf-1, y la expresión regulada al alza de las proteínas de choque térmico Hsp70 y Hsp27. BIIB021 inhibe las células de linfoma de Hodgkin (KM-H2, L428, L540, L540cy, L591, L1236 y DEV) con IC50 de 0,24 a 0,8 μM. BIIB021 muestra una baja actividad en linfocitos de individuos sanos. BIIB021 inhibe la actividad constitutiva de NF-κB a pesar de IκB defectuoso. BIIB021 induce la expresión de ligandos para la activación del receptor de células NK NKG2D en células de linfoma de Hodgkin, lo que aumenta la susceptibilidad a la muerte mediada por células NK. BIIB021 mejoró la radiosensibilidad in vitro de las líneas celulares HNSCCA (UM11B y JHU12) con una reducción correspondiente en la expresión de proteínas de respuesta radiactiva clave, aumento de células apoptóticas y aumento de la detención de G2. BIIB021 es considerablemente más activo que 17-AAG contra el carcinoma adrenocortical H295R, tanto in vitro como in vivo. La actividad citotóxica de BIIB021 no se ve influenciada por la pérdida de sobreexpresión de NQO1 o Bcl-2, lesiones moleculares que no evitan la pérdida de clientes pero que, no obstante, están asociadas con una reducción de la muerte celular por 17-AAG. BIIB021 también es activo en líneas celulares resistentes a 17-AAG (NIH-H69, MES SA Dx5, NCI-ADR-RES, Nalm6 y etc.). La administración oral de BIIB021 conduce a la inhibición del crecimiento tumoral en muchos modelos de xenoinjerto tumoral, incluidos N87, BT474, CWR22, U87, SKOV3 y Panc-1. BIIB021 inhibe eficazmente el crecimiento del tumor L540cy a una dosis de 120 mg / kg. BIIB021 mejora significativamente el efecto de crecimiento antitumoral de la radiación en el xenoinjerto JHU12. Protocolo (solo como referencia) Ensayo de quinasa: [1]

Hsp90 Binding Assay

For fluorescence polarization competition measurements, the FITC-geldanamycin probe (20 nM) is reduced with 2 mM TCEP at room temperature for 3 hours, after which the solution is aliquoted and stored at -80 °C until used. Recombinant human Hsp90α (0.8 nM) and reduced FITC-geldanamycin (2 nM) are incubated in a 96-well microplate at room temperature for 3 hours in the presence of assay buffer containing 20 mM HEPES (pH 7.4), 50 mM KCl, 5 mM MgCl2, 20 mM Na2MoO4, 2 mM DTT, 0.1 mg/mL BGG, and 0.1% (v/v) CHAPS. Following this preincubation, BIIB021 in 100% DMSO is then added to final concentrations of 0.2 nM to 10 μM (final volume 100 μL, 2% DMSO). The reaction is incubated for 16 hours at room temperature and fluorescence is then measured in an Analyst plate reader, excitation = 485 nm, emission = 535 nm. High and low controls contained no BIIB021 or no Hsp90, respectively. The data are fit to a four-parameter curve and IC50 is generated.

HER-2 Degradation Assay

MCF-7 cells (5 × 105) in complete DMEM are seeded per well in 24-well plates. The cells are propagated for 24 hours before BIIB021 addition. BIIB021 (1 mM) is prepared in DMSO and serially diluted in complete DMEM. Cells are incubated in the pr

Ensayo celular: [1]

Cell lines	BT474, MCF-7, N87, HT29, H1650, H1299, H69 and H82 cells
Concentrations	3 nM - 1 μM
Incubation Time	5 days
Method	A modified tetrazolium salt assay is used to measure the IC50. Tumor cells are added to 96-well plates and propagated for 24 hours before BIIB021 addition. BIIB021 is added to the plated cells. DMSO (0.03-0.003%) is included as a vehicle control. After incubation phenazine methosulfate (stock concentration 1 mg/mL) and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (stock concentration 2 mg/mL) are mixed at a ratio of 1:20 and added to each well of a 96-well plate. Reduction of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt gives rise to a soluble formazan product that is secreted into the culture medium. After 4 hours incubation, the formazan product is quantitated spectrophotometrically at a wavelength of 490 nm. Data are acquired using SOFTmaxPRO software, and 100% viability is defined as the A490 of DMSO-treated cells stained with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (the mean A490 of cells treated with DMSO at a range of 0.03-0.003%). Percent viability of each sample is calculated from the A490 values as follows: % viability = (A490 nm sample / A490 nm DMSO-treated cells × 100). The IC50 is defined as the concentration that gives rise to 50% inhibition of cell viabilit

Estudio con animales: [1]

Animal Models	N87, BT474, CWR22, U87, SKOV3 and Panc-1 tumor models in BALB/c and athymic mice
Formulation	Phospho-lipon/sucrose emulsion [2]
Dosages	31, 62.5, and 125 mg/kg
Administration	Orally administered once daily
Solubility	30% propylene glycol, 5% Tween 80, 65% D5W, 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.

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)	318.76
Formula	C14H15ClN6O
CAS No.	848695-25-0

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms	CNF2024

Solubility (25°C) *	In vitro	DMSO	64 mg/mL (200.77 mM)
		Water	<1 mg/mL (
		Ethanol	2 mg/mL (6.27 mM)
	In vivo	30% propylene glycol, 5% Tween 80, 65% D5W	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.

Chemical Name	6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-2-amine

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Grupos de Producto : Señalización citoesquelética > Inhibidor de HSP