.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 532.52 NMS-P937 (NMS1286937) es un inhibidor selectivo de quinasa 1 similar al polo (PLK1) disponible por vía oral con IC50 de 2 nM, selectividad 5000 veces superior a PLK2 / PLK3. Fase 1. \ n Actividad biológica NMS-P937 muestra una actividad antiproliferativa de amplio espectro contra diferentes líneas celulares de tumores sólidos, leucemias y linfomas. NMS-P937 provoca potencialmente una detención del ciclo celular mitótico seguida de apoptosis en las células A2780. En ratones xenoinjertados con células de adenocarcinoma de colon HCT116 humano, NMS-P937 (90 mg / kg / d iv o po) muestra una inhibición significativa del crecimiento tumoral. En ratones que portan tumores de xenoinjerto de ovario HT29, Colo205 colorrectal o A2780, NMS-P937 inhibe el crecimiento tumoral de xenoinjerto. Además, NMS-P937, en combinación con fármacos citotóxicos aprobados, provoca una mayor regresión tumoral y prolonga la supervivencia de los animales. Protocolo (solo como referencia) Ensayo de quinasa: [1]
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Kinase profile
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The inhibitory activity of putative kinase inhibitors and the potency of selected compounds are determined using a trans-phosphorylation assay. Specific peptide or protein substrates are trans-phosphorylated by their specific serine-threonine or tyrosine kinase, in the presence of ATP traced with 33P-γ-ATP, at optimized buffer and cofactors conditions. At the end of the phosphorylation reaction, more than 98% unlabeled ATP and radioactive ATP is captured by adding an excess of the ion exchange dowex resin; the resin then settles down to the bottom of the reaction plate by gravity. Supernatant, containing the phosphorylated substrate, is subsequently withdrawn and transferred into a counting plate, followed by evaluation by b-counting. Inhibitory potency evaluation for all the tested kinases was performed at 25 °C using a 60 min end-point assay where the concentrations of ATP and substrates are kept equal to 2 x αKm and saturated (>5 x αKm), respectively.
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Ensayo celular: [2]
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Cell lines
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137 solid tumor cell lines, and 43 cell lines derived from leukemias and lymphomas
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Concentrations
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~10 μM
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Incubation Time
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72 hours
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Method
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Cells are seeded into 96- or 384-well plates at densities ranging from 10,000 to 30,000/cm2 for adherent and 100,000/mL for nonadherent cells in appropriate medium supplemented with 10% fetal calf serum. After 24 hours, cells were treated in duplicate with serial dilutions of NMS-P937, and 72 hours later, the viable cell number was assessed by the CellTiter-Glo Assay (Promega). IC50 values were calculated with a sigmoidal fitting algorithm (Assay Explorer MDL). Experiments were carried out independently at least twice.
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Estudio con animales: [1]
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Animal Models
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CD1 nu/nu mice xenografted with human HCT116 colon adenocarcinoma cells
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Formulation
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Dosages
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45 mg/kg bid (i.v.); 90 mg/kg daily (p.o.)
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Administration
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i.v. or p.o.
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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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532.52
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Formula
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C24H27F3N8O3
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CAS No.
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1034616-18-6
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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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N/A
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Solubility (25°C) *
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In vitro
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DMSO
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42 mg/mL
heating
(78.87 mM)
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Water
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<1 mg/mL
(
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Ethanol
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10 mg/mL
heating
(18.77 mM)
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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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4,5-dihydro-1-(2-hydroxyethyl)-8-[[5-(4-methyl-1-piperazinyl)-2-(trifluoromethoxy)phenyl]amino]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide
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Calculadora de molaridad Calculadora de dilución Calculadora de peso molecular
Grupos de Producto : Ciclo celular > Inhibidor de PLK
