.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 521.53 PF-04929113 (SNX-5422) es un inhibidor de HSP90 potente y selectivo con Kd de 41 nM e induce la degradación de Her-2 con IC50 de 37 nM. Fase 1/2. \ N Actividad biológica PF-04929113 es un inhibidor de Hsp90 de molécula pequeña basado en el andamio 6,7-dihidro-indazol-4-ona. PF-04929113 desarrollado por Serenex, se convierte en SNX-2122, que es la forma inhibidora activa de Hsp90. PF-04929113 exhibe efectos potentes sobre la estabilidad de Her-2 y provoca la regulación positiva esperada de Hsp70. PF-04929113 muestra una potente actividad antiproliferativa contra una amplia gama de tipos de células cancerosas, por ejemplo, MCF-7 (IC50 = 16 nM), SW620 (IC50 = 19 nM), K562 (IC50 = 23 nM), SK-MEL-5 (IC50 = 25 nM) y A375 (IC50 = 51 nM). PF-04929113 inhibe el crecimiento de células MM humanas in vivo, y el análisis inmunohistoquímico muestra que PF-04929113 inhibe significativamente p-ERK y p-Akt en ratones tratados. Mientras tanto, el tratamiento con PF-04929113 reduce significativamente el porcentaje de células CD31 + y MVD, de acuerdo con un efecto inhibidor sobre la angiogénesis in vivo. Una administración de 50 mg / kg de PF-04929113 administrada 3 veces por semana retrasa significativamente el crecimiento del tumor LNCaP resistente a la castración y prolonga la supervivencia específica del cáncer. El análisis inmunohistoquímico indica un aumento de la expresión de SP70 y disminuye la expresión de Ki67, Akt y AR, después del tratamiento con PF-04929113. La inhibición de la progresión tumoral por PF-04929113 puede resultar de una combinación de tasas proliferativas disminuidas (expresión reducida de Ki67 y Akt) o apoptosis aumentada (tinción aumentada de ApopTag). Protocolo (solo como referencia) Ensayo de quinasa: [1]
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Affinity for Hsp90
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Hsp90 from porcine spleen extract is isolated by affinity capture on a purine-affinity media. The Hsp90 loaded media is then challenged with PF-04929113 at a given concentration, ranging from 0.8 to 500 μM, and the amount of Hsp90 liberated at each concentration is determined by Bradford protein assay. The resulting IC50 values are corrected for the ATP ligand concentration and presented as apparent Kd values.
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Ensayo celular: [1]
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Cell lines
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MCF-7, SW620, K562, SK-MEL-5 and A375 cancer cell lines
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Concentrations
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0-300 nM
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Incubation Time
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72 or 144 hours
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Method
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All assays are done in 96-well plates. All cell lines are purchased from ATCC. Proliferation rates are measured by seeding cells into 96-well plates, followed by compound addition 24 h later. After addition of PF-04929113, cells are allowed to grow for either an additional 72 or 144 h depending on rate of growth. At harvest, media is removed and DNA content for individual wells is determined using CyQuant DNA dye. Levels of Hsp90 client proteins and phosphor-regulated proteins in A375 are measured by high content analysis (HCA) using an ArrayScan 4.5 instrument after 24 hours of treatment with PF-04929113, followed by methanol fixation. After fixation in 4% PBS-buffered formalin and permeablization with 0.1% TX-100, cells are probed with anti-Her2, antiphospho-S6 (pS6), antipERK, and anti-Hsp70 primary antibodies, followed by TRITC or FITC conjugated secondary antibodies. Nuclei are also stained with Hoechst DNA binding dye. For each well, 250-500 individual nuclei are identified along with the average staining intensity for the client and phospho-proteins for each cell. Average client staining intensities are then calculated for each well.
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Estudio con animales: [2]
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Animal Models
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5 × 106 MM.1S cells are inoculated subcutaneously in the Fox Chase SCID mice (6-7 weeks old).
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Formulation
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PF-04929113 is dissolved in 1% carboxy methylcellulose/0.5% Tween 80 at 10 mg/mL and stored at 4 °C for in vivo stud
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Dosages
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20 or 40 mg/kg
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Administration
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PF-04929113 is administered orally 3 times per week, total 3 weeks.
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Solubility
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0.5% CMC/0.25% Tween 80,
25 mg/mL
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* 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.
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Conversión de diferentes modelos de animales basados en BSA (valor basado en datos del Borrador de Directrices de la FDA)
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Species
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Baboon
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Dog
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Monkey
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Rabbit
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Guinea pig
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Rat
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Hamster
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Mouse
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Weight (kg)
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12
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10
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3
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1.8
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0.4
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0.15
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0.08
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0.02
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Body Surface Area (m2)
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0.6
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0.5
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0.24
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0.15
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0.05
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0.025
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0.02
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0.007
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Km factor
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20
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20
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12
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12
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8
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6
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5
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3
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Animal A (mg/kg) = Animal B (mg/kg) multiplied by
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Animal B Km
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Animal A Km
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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.
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Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×
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mouse Km(3)
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= 11.2 mg/kg
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rat Km(6)
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Información química
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Molecular Weight (MW)
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521.53
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Formula
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C25H30F3N5O4
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CAS No.
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908115-27-5
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Storage
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3 years -20℃Powder
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6 months-80℃in solvent (DMSO, water, etc.)
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Synonyms
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Solubility (25°C) *
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In vitro
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DMSO
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104 mg/mL
(199.41 mM)
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Water
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<1 mg/mL
(
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Ethanol
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5 mg/mL
(9.58 mM)
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In vivo
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0.5% CMC/0.25% Tween 80
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25 mg/mL
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* <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.
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Chemical Name
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(1r,4r)-4-(2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-1-yl)phenylamino)cyclohexyl 2-aminoacetate
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Calculadora de molaridad Calculadora de dilución Calculadora de peso molecular
Grupos de Producto : Señalización citoesquelética > Inhibidor de HSP
