GNF-5837 1033769-28-6

.cp_wz table {border-top: твердое тело 1px #ccc; border-left: твердое тело 1px #ccc; } .cp_wz таблица td {border-right: 1px solid #ccc; нижняя граница: сплошной 1px #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 Молекулярный вес: 535,49 GNF-5837 является селективным и перорально биодоступным пан-TRK ингибитором TrkA и TrkB с IC50 8 нМ и 12 нМ, соответственно. \ n Биологическая активность

Description	GNF-5837 is a selective, and orally bioavailable pan-TRK inhibitor for TrkA, and TrkB with IC50 of 8 nM, and 12 nM, respectively.
Targets	TrkC [1]	TrkB [1]	TrkA [1]	PDGFRβ [1]	Kit [1]	&nbsp&nbsp&nbspView More
IC50	7 nM	9 nM	11 nM	0.87 μM	0.91 μM
In vitro	In Ba/F3 cells overexpressing the constitutively active Tel-TRKC fusion, GNF-5837 shows potent anti-Trk activity and potent antiproliferation activity with IC50 of 0.042 μM.
In vivo	In both male Balb/c mice and Sprague–Dawley rats, GNF-5837 has the low drug clearance, and moderate biovailability. In mice bearing Rie xenografts expressing TrkA and NGF, GNF-5837 (100 mg/kg/d p.o.) significantly inhibits tumor growth.
Features

Протокол (только для справки) Анализ киназы: [1]

Inhibition of biochemical TrkA, TrkB and TrkC

TrkA and TrkC biochemical assays are carried out by HTRF method. The reaction mixtures contains 1 μM peptide substrate, 1 μM ATP, and either 1.8 nM TrkA or 34 nM TrkC in the reaction buffer (50mM HEPES pH 7.1, 10mM MgCl2, 2 mM MnCl2, 0.01% BSA, 2.5 mM DTT and 0.1 mM Na3VO4) at a final volume of 10 μL. All reactions are carried out at room temperature in white ProxiPlate™ 384-well Plus plates and are quenched with 5 μL of 0.2 M EDTA at 60 min. Five μL of the detection reagents (2.5 ng PT66K and 0.05 μg SAXL per well) are added, the plates are incubated at room temperature for 1 h and then read in EnVision reader. Compounds are diluted into assay mixture (final DMSO 0.5%), and IC50 values are determined by 12-point (from 50 to 0.000282 μΜ) inhibition curves in duplicate under the assay conditions. TrkB biochemical assay is carried out by caliper microfluidic method. The reaction mixtures contained 1 μM peptide substrate, 10 μM ATP, and 2 nM TrkB in a reaction buffer containing 100 mM HEPES, pH 7.5, 5 mM MgCl2, 0.01% Triton X-100, 0.1% BSA, 1 mM DTT, 10 μΜNa3VO4, and 10 μΜBeta-Glycerophosphate. The reactions are carried out at room temperature for 3 hrs, and the products are determined by Caliper EZ-reader. Compounds are diluted into assay mixture (final DMSO 1%), and IC50 values are determined by 12-point (from 50 to 0.000282 μΜ) inhibition curves in duplicate under the assay conditions.

Клеточный анализ: [1]

Cell lines	Wt Ba/F3 cells and Ba/F3 cells transformed with constitutively expressed luciferase reporter and BCR-ABL or Tel-KDR or other Tel fusion kinases
Concentrations	~10 μΜ
Incubation Time	48 hours
Method	Compounds are tested for their ability to inhibit the proliferation of wt Ba/F3 cells and Ba/F3 cells transformed with constitutively expressed luciferase reporter and BCR-ABL or Tel-KDR or other Tel fusion kinases. Parental Ba/F3 cells are maintained in media containing recombinant mouse IL3 and the kinase transformed Ba/F3 cells are maintained in media without IL-3. 7.5 nL of compounds are spotted to each well of 1536-well assay plates by Liquid handling System Echo 555 (Labcyte). 700 cells are then plated into each well of the assay plates in 7 μL culture media per well and compounds are tested at 0.17 nM to 10 uM in 3-fold serial dilutions. The cells were then incubated for 48 hours at 37 °C. 3 μL of Bright-Glo® is added to each well and the plates are read using ViewLux.

Исследование на животных: [1]

Animal Models	Mice bearing Rie xenografts expressing TrkA and NGF.
Formulation	75% polyethylene glycol 300 (PEG300) and 25% of dextrose (5 mg/ml)
Dosages	100 mg/kg/d
Administration	p.o.

Конверсия различных модельных животных на основе BSA (значение на основе данных из проекта рекомендаций 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

Например, чтобы изменить дозу ресвератрола, используемую для мыши (22,4 мг / кг), на дозу, основанную на BSA для крысы, умножьте 22,4 мг / кг на коэффициент Km для мыши, а затем разделите на коэффициент Km для крыса. Этот расчет дает эквивалентную дозу ресвератрола для крыс 11,2 мг / кг.

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

Химическая информация

Molecular Weight (MW)	535.49
Formula	C28H21F4N5O2
CAS No.	1033769-28-6

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

Solubility (25°C) *	In vitro	DMSO	100 mg/mL (186.74 mM)
		Water	<1 mg/mL (
		Ethanol	9 mg/mL heating (16.8 mM)
* <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-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-yl]amino]-4-methylphenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]-urea

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