.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; preenchimento: 5px 0px 0px 5px;} \ n Peso molecular: \ n 473,98 Pazopanibe (GW786034) é um novo inibidor multi-alvo de VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit e c-Fms com IC50 de 10 nM , 30 nM, 47 nM, 84 nM, 74 nM, 140 nM e 146 nM, respectivamente. \ N Atividade biológica Pazopanib inibe potentemente a fosforilação induzida por VEGF de VEGFR2 em células HUVEC com IC50 de 8 nM. Pazopanib mostra inibição do crescimento dependente da dose em todas as linhas celulares de sarcoma sinovial, incluindo células SYO-1 e HS-SY-II. A proliferação de células SYO-1 e HS-SY-II é inibida mesmo com 1 µg / mL de Pazopanibe e é completamente abolida com 5 µg / mL. Pazopanibe induz a parada em G1 e, assim, suprime o crescimento de células de sarcoma sinovial. A fosforilação de Akts, GSK-3β, JNKs, p70 S6 quinase e mTOR é suprimida em células SYO-1 tratadas com Pazopanibe em comparação com as células tratadas com veículo. Pazopanibe entre 20 mg / mL e 22,5 mg / mL mostra uma redução crescente da viabilidade celular do EPR. Os ratos tratados com 30 mg / kg ou 100 mg / kg de Pazopanib revelaram uma diminuição significativa na carga tumoral em comparação com os ratos tratados com veículo ou 10 mg / kg de Pazopanib. O tratamento com Pazopanib é bem tolerado e não há diferença significativa no peso corporal entre os ratos de cada grupo. Ensaio de cinase de protocolo (apenas para referência): [1]
|
Kinase enzyme assays
|
VEGFR enzyme assays for VEGGR1, VEGFR2, and VEGFR3 are run in homogeneous time-resolved fluorescence (HTRF) format in 384-well microtiter plates using a purified, baculovirus-expressed glutathione-S-transferase (GST) fusion protein encoding the catalytic c-terminus of human VEGFR receptor kinases 1, 2, or 3. Reactions are initiated by the addition of 10 μL of activated VEGFR2 kinase solution [final concentration, 1 nM enzyme in 0.1 M HEPES, pH 7.5, containing 0.1 mg/mL bovine serum albumin (BSA), 300 μM dithiothreitol (DTT)] to 10 μL substrate solution [final concentration, 360 nM peptide, (biotin-aminohexyl-EEEEYFELVAKKKK-NH2), 75 μM ATP, 10 μM MgCl2], and 1 μL of titrated Pazopanib in DMSO. Plates are incubated at room temperature for 60 min, and then the reaction is quenched by the addition of 20 μL of 100 mM ethylene diamine tetraacetic acid (EDTA). After quenching, 20 μL HTRF reagents (final concentration, 15 nM Streptavidin-linked allophycocyanin, 1 nM Europium-labeled antiphosphotyrosine antibody diluted in 0.1 mg/mL BSA, 0.1 M HEPES, pH 7.5) is added and the plates incubated for a minimum of 10 min. The fluorescence at 665 nM is measured with a Wallac Victor plate reader using a time delay of 50 μs.
|
Ensaio de células: [1]
|
Cell lines
|
HUVEC cells
|
|
Concentrations
|
0-10 μM
|
|
Incubation Time
|
1 hour
|
|
Method
|
Phosphorylation of VEGFR2 is assessed in HUVEC stimulated with VEGF. HUVEC are plated in type-I collagen-coated 10 cm plates in Clonetics EGM-MV medium at 1.0-1.5 × 106 cells/plate. After 24 hours, the confluent cells are serum starved overnight by replacing the growth medium with Clonetics EBM medium containing 0.1% BSA, 500 μg/mL hydrocortisone. Cells are treated with Pazopanib at various concentrations for 1 hour, followed by addition of 10 ng/mL VEGF or vehicle for 10 min. Cells are solubilized in lysis buffer. VEGFR2 is immunoprecipitated using antiflk-1 antibody and analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) followed by Western blotting and detection with antiflk-1 or with antiphosphotyrosine (anti-P-tyr-biotin) antibody. The VEGFR2 phosphorylation level is quantified by densitometry and normalized to the total VEGFR2 level.
|
Estudo Animal: [2]
|
Animal Models
|
Immunodeficient mice bearing SYO-1 cells
|
|
Formulation
|
|
|
Dosages
|
0 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg
|
|
Administration
|
Oral administration
|
|
Solubility
|
30% PEG400/0.5% Tween80/5% propylene glycol,
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.
|
Conversão de diferentes modelos de animais com base em BSA (valor com base em dados das diretrizes preliminares da 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 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.
|
Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×
|
mouse Km(3)
|
= 11.2 mg/kg
|
|
rat Km(6)
|
Informação Química
|
Molecular Weight (MW)
|
473.98
|
|
Formula
|
C21H23N7O2S.HCl
|
|
CAS No.
|
635702-64-6
|
|
Storage
|
3 years -20℃Powder
|
|
6 months-80℃in solvent (DMSO, water, etc.)
|
|
Synonyms
|
|
|
Solubility (25°C) *
|
In vitro
|
DMSO
|
17 mg/mL
(35.86 mM)
|
|
Water
|
<1 mg/mL
(
|
|
Ethanol
|
<1 mg/mL
(
|
|
In vivo
|
30% PEG400/0.5% Tween80/5% propylene glycol
|
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
|
5-(4-((2,3-dimethyl-2H-indazol-6-yl)(methyl)amino)pyrimidin-2-ylamino)-2-methylbenzenesulfonamide hydrochloride
|
Calculadora de molaridade Calculadora de diluição Calculadora de peso molecular
Grupo de Produto : Angiogênese > Inibidor Bcr-Abl
