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    LGK974 (WNT974; LGK974)
    LGK974 (WNT974; LGK974)

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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 #: V1353
    CAS #: 1243244-14-5Purity ≥98%

    Description: LGK-974 (formerly known as WNT-974; LGK-974 and NVP-LGK974) is a novel potent, orally bioavailable and specific/selective PORCN (Porcupine) inhibitor with potential anticancer activity. It inhibits Wnt signaling with an IC50 of 0.4 nM in TM3 cells. LGK974 binds to and inhibits PORCN in the endoplasmic reticulum (ER), which blocks post-translational acylation of Wnt ligands and inhibits their secretion. This prevents the activation of Wnt ligands, interferes with Wnt-mediated signaling, and inhibits cell growth in Wnt-driven tumors. LGK-974 is being investigated for the treatment of cancers driven by the Wnt pathway in a Wnt ligand-dependent manner.    

    References: Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9; Proc Natl Acad Sci U S A. 2013 Jul 30;110(31): 12649-54.


    Publications Citing Use of InvivoChem LGK974 (WNT974)Cancer Cell. 2021 Apr 12;39(4):529-547.e7. doi: 10.1016/j.ccell.2021.02.006.  

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    Molecular Weight (MW)396.44
    FormulaC23H20N6O
    CAS No.1243244-14-5;  2375595-49-4 (2HCl);
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 79 mg/mL (199.3 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)2% DMSO+corn oil: 5 mg/mL
    Synonyms

    NVP-LGK974; NVPLGK974; NVP LGK974; LGK974; LGK-974; LGK 974; WNT974; WNT 974; WNT-974

    Chemical Name: 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 

    SMILES Code: O=C(NC1=NC=C(C2=NC=CN=C2)C=C1)CC3=CN=C(C4=CC(C)=NC=C4)C(C)=C3

    Exact Mass: 396.16986 


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    In Vitro

    In vitro activity: LGK974 effectively displaces [3H]-GNF-1331 with IC50 of 1 nM in the PORCN radioligand binding assay, and shows no major cytotoxicity in cells up to 20 µM. LGK974 shows comparable inhibitory activities against all tested Wnts with IC50 ranging from 0.05 to 2.4 nM, which is consistent with the genetic loss of PORCN phenotype. LGK974 specifically inhibits the growth of three RNF43-mutant cell lines, HPAF-II, PaTu 8988S, and Capan-2.


    Kinase Assay: Radioligand binding assay: using the aforementioned membrane preps, filtration binding assays are performed. To reduce nonspecific binding, 96-well filtration plates are precoated as suggested by the manufacturer with 0.1% BSA and then washed four times with 0.1% BSA. Membrane preps (50 μg total protein) are incubated in polypropylene 96-well plates with 6.6 nM 3H-GNF-1331 in the presence or absence of a testing compound in binding buffer (50 mM Tris, pH 7.5, 5 mM MgCl2, 1 mM EDTA, 0.1% BSA) plus EDTA-free protease inhibitor mixture in a final volume of 150 μL for 3 h at room temperature. Binding reaction mixtures are then transferred to the precoated 96-well filtration plates, filtered, and washed using a 96-pin FilterMate Harvester. Radioactive signals are obtained using a Microplate Scintillation Counter TopCount. Curve fitting is performed using Prism.


    Cell Assay: Cells are plated in growth medium in a 96-well plate at a density of 6,000–12,000 cells per well and treated with DMSO or 1 μM LGK974. After 3 d, the cells are treated with fresh growth medium containing 20 μM EdU, which is included in the Click-iT EdU Alexa Fluor 488 HCS assay kit, and the plate was incubated for 2 h at 37 °C in a humidified atmosphere containing 5% CO2. Cells are fixed with final 4% (mass/vol) paraformaldehyde for 30 min, washed with PBS, permeabilized, and stained with 50 μg/mL Hoechst in PBS for 30 min. After wash, the cells are proceeded to EdU detection according to the instruction of Click-iT EdU assay kit. Triplet wells are performed for each condition.

    In VivoIn a murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30), LGK974 (3 mg/kg) inhibits Wnt signaling in vivo and induces tumor regression without significant body weight loss in the mice. LGK974 (5 mg/kg, p.o., BID) also inhibits tumor growth of RNF43-mutant pancreatic tumors (HPAF-II and Capan-2) in vivo.
    Animal modelA murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30)
    Formulation & DosageDissolved in 010% (vol/vol) citrate buffer (pH 2.8)/90% (vol/vol) citrate buffer (pH 3.0) or 0.5% MC/0.5% Tween 80; 3 mg/kg; Oral gavage 
    ReferencesProc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9; Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12649-54.


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

    LGK-974


    LGK974 inhibits tumor growth of RNF43-mutant pancreatic tumors in vivo.  2013 Jul 30;110(31):12649-54.

    LGK-974


    LGK974 specifically inhibits the growth of pancreatic cancer cell lines harboring RNF43 mutation.  2013 Jul 30;110(31):12649-54.

     LGK-974


    Characterization of RNF43 mutations in pancreatic cancer.  2013 Jul 30;110(31):12649-54.


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