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    GNF-5837
    GNF-5837

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0641
    CAS #: 1033769-28-6Purity ≥98%

    Description: GNF-5837 is a novel, potent, selective, and orally bioavailable pan-TRK inhibitor for TrkA, and TrkB with IC50 of 8 nM, and 12 nM, respectively. The TRK-inhibiting properties of GNF-5837 therefore make it a useful tool to investigate TRK biology in cancer and other non-oncology indications. The anti-TRKA activity of GNF-5837 was detected in Ba/F3 and RIE cells expressing both TRKA and NGF. In Ba/F3 cells, this compound exhibited intensively anti-proliferation activity with an IC50 of 0.042 μM. GNF-5837 inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF.

    References: ACS Med Chem Lett. 2012 Jan 1;3(2):140-5.

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    Molecular Weight (MW)535.49
    FormulaC28H21F4N5O2
    CAS No.1033769-28-6
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 100 mg/mL (186.7 mM)
    Water: <1 mg/mL
    Ethanol:  9 mg/mL(16.8 mM)
    Other infoChemical Name: (Z)-1-(3-((3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)amino)-4-methylphenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea
    InChi Key: YYDUWLSETXNJJT-MTJSOVHGSA-N
    InChi Code: InChI=1S/C28H21F4N5O2/c1-15-4-6-19(35-27(39)37-25-11-16(28(30,31)32)5-9-22(25)29)13-23(15)34-18-7-8-20-21(12-17-3-2-10-33-17)26(38)36-24(20)14-18/h2-14,33-34H,1H3,(H,36,38)(H2,35,37,39)/b21-12-
    SMILES Code: O=C(NC1=CC(C(F)(F)F)=CC=C1F)NC2=CC=C(C)C(NC3=CC(NC/4=O)=C(C=C3)C4=C\C5=CC=CN5)=C2
    SynonymsGNF-5837; GNF 5837; GNF5837; 


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    In Vitro

    In vitro activity: 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.


    Kinase Assay: 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 0.2mM 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. 


    Cell Assay:  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. Cell line: 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

    In VivoIn 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.
    Animal modelMice bearing Rie xenografts expressing TrkA and NGF.
    Formulation & DosageDissolved in 75% polyethylene glycol 300 (PEG300) and 25% of dextrose (5 mg/ml); 100 mg/kg; oral gavage
    References

    ACS Med Chem Lett. 2012 Jan 1;3(2):140-5.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    GNF-5837

    Efficacy of GNF-5837 (22) in Rie-TRKAmNGF xenograft model. ACS Med Chem Lett. 2012 Feb 9; 3(2): 140–145.

    GNF-5837

    X-ray crystal structure of compound 20 (stick representation; carbon in yellow, oxygen in red, nitrogen in blue, and fluorine in light blue) binding to the active site of TRKC kinase domain. ACS Med Chem Lett. 2012 Jan 1;3(2):140-5.


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