Pimasertib (AS-703026) 1236699-92-5

.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 431,20 Pimasertib (AS-703026) é um inibidor alostérico não competitivo de ATP altamente seletivo, potente de MEK1 / 2 com IC50 de 5 nM-2 μM na célula MM linhas. Fase 2. \ n Atividade biológica AS703026 é um inibidor MEK1 / 2 novo, seletivo e biodisponível oralmente que se liga ao sítio alostérico distinto de MEK e, portanto, exibe seletividade de quinase requintada. AS703026 inibe o crescimento e a sobrevivência de células de mieloma múltiplo (MM) humano, incluindo U266 e INA-6, com IC50 de 5 nM e 11 nM, respectivamente. Esse efeito inibidor por AS703026 é mediado pela parada do ciclo celular G0-G1 e é acompanhado por expressão reduzida do oncogene MAF. AS703026 induz ainda apoptose via caspase-3 e clivagem de PARP em células MM, na presença ou ausência de células estromais da medula óssea (BMSCs). AS703026 pode ser uma terapia eficaz no câncer colorretal causado pela mutação K-Ras. AS703026 (10 μM) inibe efetivamente a via ERK, proliferação e transformação em células de câncer colorretal DLD-1 humano que carregam um alelo mutante de K-Ras (D-MUT). AS703026 (15 e 30 mg / kg) inibe significativamente o crescimento do tumor em um modelo de xenoenxerto de plasmocitoma humano de células H929 MM. Isso pode ser correlacionado com pERK1 / 2 regulado para baixo, clivagem de PARP induzida e microvasos diminuídos. AS703026 (10 mg / kg) inibe o crescimento do tumor e diminui marcadamente o nível de p-ERK em um modelo de camundongo de xenoenxerto de tumor colorretal mutado de K-Ras humano (D-MUT). Ensaio de cinase de protocolo (apenas para referência): [3]

MEK1 enzyme assays

AS703026 is dissolved in 2.5% DMSO. Activated diphosphorylated MEK (pp-MEK) assays contained 40 μM 33P-γATP (AppKm 8.5 μM), 0.5 nM human-activated MEK1 or MEK2, 1 μM kinase-dead ERK2 (AppKm 0.73 μM). All assays are done in buffer containing 20 mM HEPES (pH 7.2), 5 mM 2-mercaptoethanol, 0.15 mg/mL BSA, and 10 mM MgCl2. The final concentration of 33P- ATP is 0.02 μCi/μL for all the assays. pp-MEK kinase reactions are stopped after 40 min by transferring 30 μL of reaction mixture to Durapore 0.45-μm filters plates containing 12.5% TCA. Filters are dried and read with liquid scintilant on a TopCount. Concentration response data are analyzed for IC50. 0.2 nM recombinant human MEK1 or MEK2 is preincubated with vehicle or with AS703026 for 40 minutes in reaction buffer to determine IC50 of initially unphosphorylated MEK (u-MEK). Phosphorylation/activation is initiated by the addition of a final concentration of 20 nM final B-RafV600E and 30 μM final ATP for 10 min. B-Raf activity is then quenched by addition of the B-Raf inhibitor SB590885 (final concentration 100 nM), and MEK kinase activity is assayed by the addition of 1 μM KD-ERK2 and 0.02 μCi/μL 33P-ATP in reaction buffer. The kinase reactions are stopped after 90 min by transferring 30μL of reaction mixture to a Durapore filter plate, and read as above.

Ensaio de células: [1]

Cell lines	U266 and INA-6 cells
Concentrations	2 nM - 20 μM (stock: 10 mM in DMSO)
Incubation Time	48 hours
Method	Cytotoxicity assays for AS703026 are assessed by measuring both [3H]thymidine incorporation and MTT dye absorbance. Cells (1 × 104 per well) are cultured in 96-well plates for 3 days. For the [3H]thymidine incorporation assay, cells are pulsed with 18.5 kBq/well [3H]thymidine for 6 hours, harvested onto glass fibre filters, and counted in a β-scintillation counter. Cell cycle analysis is assessed by propidium iodide (PI) staining using flow cytometry. AS703026-induced apoptosis is determined by annexin-V/PI staining and flow cytometric data analysis.

Estudo Animal: [1]

Animal Models	H929 MM xenografts are established in CB17 (SCID) mice
Formulation	10 mg/mL, dissolved in 0.5% carboxymethylcellulose / 0.25% Tween20
Dosages	15 or 30 mg/kg
Administration	Oral gavage twice daily
Solubility	0.5% CMC/0.25% Tween 80, 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)	431.20
Formula	C15H15FIN3O3
CAS No.	1236699-92-5

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

Solubility (25°C) *	In vitro	DMSO	86 mg/mL (199.44 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	In vivo	0.5% CMC/0.25% Tween 80	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	(S)-N-(2,3-dihydroxypropyl)-3-(2-fluoro-4-iodophenylamino)isonicotinamide

Calculadora de molaridade Calculadora de diluição Calculadora de peso molecular

Grupo de Produto : MAPK > Inibidor MEK