JNJ-7706621 443797-96-4

.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 394,36 JNJ-7706621 é um inibidor de pan-CDK com a maior potência em CDK1 / 2 com IC50 de 9 nM / 4 nM e mostrando seletividade> 6 vezes para CDK1 / 2 do que CDK3 / 4/6. Também inibe potentemente Aurora A / B e não tem atividade em Plk1 e Wee1. \ N Atividade biológica JNJ-7706621 também mostra alguma inibição para VEGF-R2, FGF-R2 e GSK3β, com IC50 de 154-254 nM. JNJ-7706621 mostra o efeito inibitório em um painel de tipos de células de câncer humano, incluindo HeLa, HCT-116, SK-OV-3, PC3, DU145, A375, MDA-MB-231, MES-SA e MES-SA / Dx5 , com IC50 de 112-514 nM, independente do status de p53, retinoblastoma ou glicoproteína P. JNJ-7706621 é várias vezes menos potente na inibição do crescimento de tipos de células normais, incluindo MRC-5, HASMC, HUVEC e HMVEC, com IC50 de 3,67-5,42 μM. Em células HeLa ou U937, JNJ-7706621 (0,5-3 μM) retarda a saída de G1, interrompe as células em G2-M, induz endoreduplicação, ativa apoptose e reduz a formação de colônias. Em uma linha celular HeLa, o tratamento incremental com concentrações crescentes de JNJ-7706621 leva a uma resistência de 16 vezes, que pode ser mediada por ABCG2. No modelo de xenoenxerto de camundongo de tumor humano de melanoma A375, JNJ-7706621 (100 ou 125 mg / kg) causa a regressão do tumor. Ensaio de cinase de protocolo (apenas para referência): [1]

In vitro kinase assay for CDK1 and Aurora kinases

For CDK1 kinase activity, a method is developed using the CDK1/cyclin B complex purified from baculovirus to phosphorylate a biotinylated peptide substrate containing the consensus phosphorylation site for histone H1, which is phosphorylated in vivo by CDK1. Inhibition of CDK1 activity is measured by observing a reduced amount of 33P-γ-ATP incorporation into the immobilized substrate in streptavidin-coated 96-well scintillating microplates. CDK1 enzyme is diluted in 50 mM Tris-HCl (pH 8), 10 mM MgCl2, 0.1 mM Na3VO 4, 1 mM DTT, 1% DMSO, 0.25 μM peptide, 0.1 μCi per well 33P-γ-ATP, and 5 μM ATP in the presence or absence of various concentrations of JNJ-7706621 and incubated at 30 °C for 1 hour. The reaction is terminated by washing with PBS containing 100 mM EDTA and plates are counted in a scintillation counter. Linear regression analysis of the percent inhibition by JNJ-7706621 is used to determine IC50. The Aurora kinase assays are done with 10 μM ATP and a peptide containing a dual repeat of the kemptide phosphorylation motif.

Ensaio de células: [3]

Cell lines	HeLa, HCT-116, A375, SK-OV-3, MDA-MB-231, and PC-3 cells
Concentrations	1 nM - 10 μM, dissolved in DMSO
Incubation Time	48 hours
Method	The ability of JNJ-7706621 to inhibit the proliferation of cell growth is determined by measuring incorporation of 14C-labelled thymidine into newly synthesized DNA within the cells. Cells are trypsinized and counted and 3-8 × 103 cells are added to each well of a 96-well CytoStar tissue culture treated scintillating microplate in complete medium in a volume of 100 μL. Cells are incubated for 24 hours in complete medium at 37 °C in an atmosphere containing 5% CO2. Next, 1 μL of JNJ-7706621 is added to the wells of the plate. Cells are incubated for 24 more hours. Methyl 14C-thymidine 56 mCi/mmol is diluted in complete medium and 0.2 μCi/well is added to each well of the CytoStar plate in a volume of 20 μL. The plate is incubated for 24 hours at 37 °C in JNJ-7706621 plus 14C-thymidine. The contents of the plate are discarded and the plate is washed twice with 200 μL PBS. 200 μL of PBS is added to each well. The top of the plate is sealed with a transparent plate sealer and a white plate backing sealer is applied to the bottom of the plate. The degree of methyl 14C-thymidine incorporation is quantified on a Packard Top Count.

Estudo Animal: [1]

Animal Models	Mouse xenograft model of A375 cells
Formulation	Dissolved in 0.5% methylcellulose containing 0.1% polysorbate 80 in sterile water.
Dosages	100 or 125 mg/kg
Administration	Orally or by intraperitoneal injection injection
Solubility	0.5% methylcellulose/0.2% Tween 80, 14 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)	394.36
Formula	C15H12F2N6O3S
CAS No.	443797-96-4

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

Solubility (25°C) *	In vitro	DMSO	79 mg/mL (200.32 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	In vivo	0.5% methylcellulose/0.2% Tween 80	14 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	4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide

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Grupo de Produto : Ciclo de célula > Inibidor CDK