.cp_wz table {border-top: 1px solid #ccc; border-left: 1px solid #ccc; } .cp_wz table td {border-right: 1px solid #ccc; borda inferior: 1px sólido #ccc; preenchimento: 5px 0px 0px 5px;} .cp_wz tabela 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) é uma disponível por via oral, selectivos polo-like-cinase 1 (PLK1) inibidor com IC50 de 2 nM, selectividade 5000 vezes em relação a PLK2 / PLK3. Fase 1. \ n actividade biológica NMS-P937 apresenta uma actividade antiproliferativa de largo espectro contra diferentes tumores sólidos, leucemias e linfomas linhas celulares. NMS-P937 potente provoca uma paragem do ciclo celular mitótico seguido por apoptose em células A2780. Em ratinhos xenoenxertados com células HCT116 humano de adenocarcinoma do cólon, NMS-P937 (90 mg / kg / d iv ou po) apresenta uma inibição significativa do crescimento do tumor. Em HT29 ratinhos rolamento, Colo205 colo-rectal, ou tumores de xenoenxerto A2780 ovário, o crescimento do tumor de xenoenxerto de NMS-P937 inibe. Além disso, NMS-P937, em combinação com drogas citotóxicas aprovados, provoca a regressão do tumor aumentada, e prolonga a sobrevivência dos animais. Ensaio de cinase de protocolo (apenas para referência): [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 Supernatant, containing the phosphorylated substrate, is subsequently withdrawn and transferred into a counting plate, followed by evaluation by b-counting.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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Ensaio 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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Estudo Animal: [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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Conversão de diferentes modelos de animais com base em BSA (valor com base em dados das diretrizes preliminares da 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 exemplo, para modificar a dose de resveratrol usada para um camundongo (22,4 mg / kg) para uma dose baseada na BSA para um rato, multiplique 22,4 mg / kg pelo fator Km para um camundongo e, em seguida, divida pelo fator Km para um rato. Este cálculo resulta em uma dose equivalente de rato para o 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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Informação 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 molaridade Calculadora de diluição Calculadora de peso molecular
Grupo de Produto : Ciclo de célula > Inibidor PLK
