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    GNF-2
    GNF-2

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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 #: V0678
    CAS #: 778270-11-4Purity ≥98%

    Description: GNF-2 is a novel, highly potent and selective allosteric/non-ATP competitive inhibitor of Bcr-Abl, it shows no activity to Flt3-ITD, Tel-PDGFR, TPR-MET and Tel-JAK1 transformed tumor cells. Unlike imatinib that competitively inhibited the ATP-binding site of BCR-ABL kinase activity, GNF-2 allosterically inhibited (through binding the myristate-binding site of ABL the proliferation of BCR-ABL positive cell and induces cell apoptosis.

    References: Nat Chem Biol. 2006;2(2):95-102; J Biol Chem. 2009;284(42):29005-14; Nature. 2010;463:501-6.

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    Molecular Weight (MW)374.32
    FormulaC18H13F3N4O2
    CAS No.778270-11-4
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 74 mg/mL (197.69 mM)
    Water:<1 mg/mL
    Ethanol: <1 mg/mL
    Other infoChemical Name: 3-(6-((4-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)benzamide
    InChi Key: WEVYNIUIFUYDGI-UHFFFAOYSA-N
    InChi Code: InChI=1S/C18H13F3N4O2/c19-18(20,21)27-14-6-4-13(5-7-14)25-16-9-15(23-10-24-16)11-2-1-3-12(8-11)17(22)26/h1-10H,(H2,22,26)(H,23,24,25)
    SMILES Code: O=C(N)C1=CC=CC(C2=NC=NC(NC3=CC=C(OC(F)(F)F)C=C3)=C2)=C1
    SynonymsGNF-2; GNF 2; GNF2; 


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    In Vitro

    In vitro activity: GNF-2 causes a dose-dependent growth inhibition of the Bcr-abl–positive cell lines with IC50 values of 273 nM (K562) and 268 nM (SUP-B15). GNF-2 inhibits the growth of Ba/F3.p210E255V and Ba/F3.p185Y253H cells with IC50 values of 268 nM and 194 nM respectively. GNF-2 (1 μM) induces apoptosis of Ba/F3.p210 cells as well as Ba/F3.p210E255V cells. GNF-2 inhibits the cellular tyrosine phosphorylation of Bcr-abl in a dose-dependent manner with IC50 of 267 nM. GNF-2 (1 μM) induces a significant decrease in the levels of phospho-Stat5 in Ba/F3.p210 cells. GNF-2 binds to the myristic binding pocket of Bcr-abl. GNF-2 inhibits the kinase activity of non-myristoylated c-Abl more potently than that of myristoylated c-Abl by binding to the myristate-binding pocket in the C-lobe of the kinase domain. GNF-2 (10 μM) requires BCR and/or the c-Abl SH3 and/or SH2 domains to inhibit BCR-Abl-dependent cell proliferation. GNF-2, but not a methylated GNF-2 analog, binds c-Abl in cellular extracts derived from 3T3 fibroblasts. GNF-2 (10 μM), in a dose-dependent manner, clearly inhibits tyrosine phosphorylation of CrkII. GNF-2 inhibits the phosphorylation of CrkII in c-AblG2A-expressing cells with IC50 of 0.051 μM. GNF-2 binds in an extended conformation in the myristate pocket with the CF3-group buried at the same depth as the final two carbons of the myristate ligand. GNF-2 (10 µM) combined with imatinib (1 µM) reduces the number of resistant clones to 1 µM imatinib by at least 90%. GNF-2 inhibits the auto-phosphorylation and proliferation of BafF3 cells expressing p210Bcr–Abl and p210Bcr–Abl mutants. GNF-2 (8 nM) in combination with GNF-5 (20 nM) results in additive effects with respect to inhibition of the Abl64–515 kinase activity.


    Kinase Assay: Recombinant proteins (100 nM for each construct) or immunoprecipitated proteins are diluted in kinase buffer (20 mM HEPES (pH 7.4), 50 mM KCl, 0.1% CHAPS, 30 mM MgCl2, 2 mM MnCl2, 1 mM DTT, and 1% glycerol). Aliquots of the diluted proteins are preincubated with either DMSO or compounds for 30 min at room temperature and then added to K-LISA PTK EAY reaction plates. The kinase reaction is initiated by adding 0.1 mM ATP and is allowed to proceed for 30 min at room temperature. The phosphorylation of GST-Abltide is monitored by SDS-PAGE and phosphorimaging analysis or autoradiography.


    Cell Assay: Cells (0.3-0.6 × 106 per mL, Ba/F3.p210, Ba/F3.p210E255V and Ba/F3.p185Y253H cells) are plated in duplicate or triplicate in 96-well plates containing increasing GNF-2 concentrations (5 nM–10 μM). After incubation at 37 ℃ in 5% CO2 for 48 hours, the effect of GNF-2 on cell viability is determined by the MTT colorimetric dye reduction method. Inhibition of cell proliferation is calculated as a percentage of growth of DMSO-treated cells, and IC50 values are determined with Microsoft Excel XLfit3.

    In VivoCombining PDMP and GNF-2 eliminated transplanted-CML-T315I-mutants in vivo and dose dependently sensitized primary cells from CML T315I patients to GNF-2-induced proliferation inhibition and apoptosis
    Animal model
    Formulation & Dosage
    ReferencesNat Chem Biol. 2006 Feb;2(2):95-102; J Biol Chem. 2009 Oct 16;284(42):29005-14; Nature. 2010 Jan 28;463(7280):501-6.


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

    GNF-2

    GNF-2 targets c-Abl in tissue culture cells. J Biol Chem. 2009 Oct 16;284(42):29005-14.

    GNF-2

    GNF-2 induces translocation of the myristoylated c-Abl to the ER. J Biol Chem.2009 Oct 16;284(42):29005-14.

    GNF-2

    N-Myristoyl group in c-Abl affects the ability of GNF-2 to inhibit c-Abl kinase activity. J Biol Chem. 2009 Oct 16;284(42):29005-14. 


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