Foretinib (GSK1363089) 849217-64-7

.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 632.65 Foretinib (GSK1363089) es un inhibidor competitivo de ATP de HGFR y VEGFR, principalmente para Met y KDR con IC50 de 0.4 nM y 0.9 nM. Menos potente contra Ron, Flt-1/3/4, Kit, PDGFRα / β y Tie-2, y poca actividad contra FGFR1 y EGFR. Fase 2. \ n Actividad biológica XL880 inhibe las tirosina quinasas de la familia de receptores de HGF con valores de CI50 de 0,4 nM para Met y 3 nM para Ron. XL880 también inhibe KDR, Flt-1 y Flt-4 con valores de IC50 de 0,9 nM, 6,8 nM y 2,8 nM, respectivamente. XL880 inhibe el crecimiento de colonias de células B16F10, A549 y HT29 con IC50 de 40 nM, 29 nM y 165 nM, respectivamente. Un estudio reciente indica que XL880 afecta el crecimiento celular de manera diferente en las líneas celulares de cáncer gástrico MKN-45 y KATO-III. XL880 inhibe la fosforilación de MET y moléculas de señalización aguas abajo en las células MKN-45, mientras que se dirige a GFGR2 en las células KATO-III. Una sola dosis de 100 mg / kg por sonda oral de XL880 da como resultado una inhibición sustancial de la fosforilación del Met del tumor B16F10 y la fosforilación del receptor inducida por ligando (p. Ej., HGFor VEGF) de Met en el hígado y Flk-1 / KDR en el pulmón, que persistieron a través de 24 horas. El tratamiento con XL880 (30-100 mg / kg, una vez al día, sonda oral) reduce la carga tumoral. La carga tumoral de la superficie pulmonar se reduce en un 50% y un 58% después del tratamiento con 30 y 100 mg / kg de XL880, respectivamente. El tratamiento con XL880 de ratones que portan tumores sólidos B16F10 también da como resultado una inhibición del crecimiento tumoral dependiente de la dosis del 64% y 87% a 30 y 100 mg / kg, respectivamente. Para ambos estudios, la administración de XL880 se tolera bien sin una pérdida significativa de peso corporal. XL880 está desarrollado para apuntar a la señalización anormal de HGF a través de Met y, simultáneamente, apuntar a varios receptores de tirosina quinasa implicados en la angiogénesis tumoral. XL880 provocó hemorragia y necrosis tumoral en xenoinjertos humanos en un plazo de 2 a 4 horas, y se observa una necrosis tumoral máxima a las 96 horas (después de cinco dosis diarias), lo que da como resultado una regresión completa. Protocolo (solo como referencia) Ensayo de quinasa: [1]

Kinase Inhibition Assay

Kinase inhibition is investigated using one of three assay formats: [33P]phosphoryl transfer, luciferase-coupled chemiluminescence, or AlphaScreen tyrosine kinase technology. IC50s are calculated by nonlinear regression analysis using XLFit.33P -Phosphoryl Transfer Kinase Assay Reactions are performed in 384-well white, clear bottom, high-binding microtiter plates (Greiner, Monroe, NC). Plates are coated with 2 μg/well of protein or peptide substrate in a 50 μL volume of coating buffer contained 40 μg/mL substrate (poly(Glu, Tyr) 4:1, 22.5 mM Na2CO3, 27.5 mM NaHCO3, 50 mM NaCl and 3 mM NaN 3. Coated plates are washed once with 50 μL of assay buffer following overnight incubation at room temperature (RT). Test compounds and enzymes are combined with 33P-γ-ATP (3.3 μCi/nmol) in a total volume of 20 μL. The reaction mixture is incubated at RT for 2 hours and terminated by aspiration. The microtiter plates are subsequently washed 6 times with 0.05% Tween-PBS buffer (PBST). Scintillation fluid (50 μL/well) is added and incorporated 33P is measured by liquid scintillation spectrometry using a MicroBeta scintillation counter.Luciferase-Coupled Chemiluminescence Assay Reactions are conducted in 384-well white, medium binding microtiter plates (Greiner). In a first step enzyme and compound are combined and incubated for 60 minutes; reactions are initiated by addition of ATP and peptide substrate (poly(Glu, Tyr) 4:1) in a final voume of 20 μL, and incubated at RT for 2-4 hours. Following the kinase reaction, a 20 μL aliquot of Kinase Glo (Promega, Madison, WI) is added and luminescence signal is measured using a Victor plate reader. Total ATP consumption is limited to 50%. AlphaScreenTM Tyrosine Kinase Assay Donor beads coated with streptavidin and acceptor beads coated with PY100 anti-phosphotyrosine antibody are used. Biotinylated poly(Glu,Tyr) 4:1 is used as the substrate. Substrate phosphorylation is measured by addition of donor/acceptor beads by luminescence following donor-acceptor bead complex formation. Kinase and test compounds are combined and preincubated for 60 minutes, followed by addition of ATP, and biotinylated poly(Glu, Tyr) in a total volume of 20 μL in 384-well white, medium binding microtiter plates (Greiner). Reaction mixtures are incubated for 1 hour at room temperature. Reactions are quenched by addition of 10 μL of 15-30 μg/mL AlphaScreen bead suspension containing 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA and 0.03% Tween-20. After 2-16 hours incubation at room temperature plates are read using an AlphaQuest reader.

Ensayo celular: [1]

Cell lines	B16F10, A549, and HT29 cells
Concentrations	40 nM
Incubation Time	12 to 14 days
Method	B16F10, A549, and HT29 cells (1.2× 103 per well) are mixed with soft agar and seeded in a 96-well plate containing 10% FBS and EXEL-2880 over a base agar layer. For normoxic conditions, the plates are incubated (37°C) for 12 to 14 days in 21% oxygen, 5% CO2, and 74% nitrogen, whereas incubation (37 °C) under hypoxic conditions is done in a hypoxia chamber in 1% oxygen, 5% CO2, and 94% nitrogen. The number of colonies is evaluated under each condition following addition of 50% Alamar Blue and fluorescence detection.

Estudio con animales: [1]

Animal Models	B16F10 tumor cells (2 × 10 5) are implanted via i.v. tail vein injection into athymic nude mice (NCr or BALB/c) 5 to 8 weeks old
Formulation	0.9% normal saline
Dosages	100 mg/kg
Administration	Administered via oral gavage
Solubility	30% propylene glycol, 5% Tween 80, 65% D5W, 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.

Conversión de diferentes modelos de animales basados ​​en BSA (valor basado en datos del Borrador de Directrices de la 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 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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Información química

Molecular Weight (MW)	632.65
Formula	C34H34F2N4O6
CAS No.	849217-64-7

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms	EXEL-2880,XL-880

Solubility (25°C) *	In vitro	DMSO	127 mg/mL (200.74 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	In vivo	30% propylene glycol, 5% Tween 80, 65% D5W	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	N-(3-fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Calculadora de molaridad Calculadora de dilución Calculadora de peso molecular

Grupos de Producto : Angiogénesis > Inhibidor de Bcr-Abl