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Purity: =99.88%
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.
| Targets |
Porcupine (PORCN, IC₅₀ = 0.1 nM), a membrane-bound O-acyltransferase essential for Wnt ligand palmitoylation and secretion [1]
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| ln Vitro |
LGK974 efficiently displaces [3H]-GNF-1331 in PORCN radioligand binding assays, with an IC50 of 1 nM. In HN30 cells, LGK974 efficiently lowers Wnt-dependent AXIN2 mRNA levels with an IC50 of 0.3 nM[1].
LGK974 inhibited Wnt signaling in HEK293 cells stably expressing a Wnt-responsive luciferase reporter (STF3A), with an EC₅₀ of 0.4 nM. Treatment reduced Wnt3a-induced luciferase activity by >95% at 100 nM. [1] The compound blocked Wnt ligand palmitoylation in vitro, as confirmed by the absence of palmitate incorporation into Wnt3a protein in PORCN-overexpressing cells treated with 10 nM LGK974 for 24 hours. [1] In lung adenocarcinoma cell lines (e.g., H2030-BrM3), LGK974 (1 μM) suppressed tumor cell proliferation by >80% after 72 hours by inhibiting autocrine Wnt production. Wnt pathway activity was assessed via Axin2 mRNA downregulation (qPCR). [2] |
| ln Vivo |
The medication LGK974, which targets the Wnt-specific acyltransferase Porcupine. Strongly suppressing Wnt signaling, well-tolerated, and highly effective in rodent tumor models is LGK974. Rats without tumors were used in toxicology tests at doses of 3 and 20 mg/kg. LGK974 was well tolerated at an effective dose of 3 mg/kg per day for 14 days, and no aberrant histopathological abnormalities were observed in tissues that depend on Wnt, such as the stomach, intestines, or skin. Rats given very high dosages (20 mg/kg per day) for 14 days showed loss of intestinal epithelial cells, which is consistent with the idea that Wnt is necessary for intestinal tissue homeostasis [1].
In MMTV-Wnt1 transgenic mice (spontaneous mammary tumors), oral LGK974 (3 mg/kg daily) induced complete tumor regression in 5/10 mice and inhibited tumor growth by 98% (vs. vehicle) after 21 days. Wnt target gene expression (Axin2, Lgr5) was reduced >90% in tumors. [1] In lung adenocarcinoma patient-derived xenograft (PDX) models, LGK974 (20 mg/kg daily orally) reduced tumor growth by 70% after 4 weeks. This efficacy correlated with decreased Wnt ligand activity in tumor stroma, evidenced by reduced Wnt target gene expression (ISH for Axin2). [2] |
| Enzyme Assay |
PORCN enzymatic activity was measured via in vitro palmitoylation assay. Recombinant PORCN was incubated with Wnt3a peptide substrate, ³H-palmitoyl-CoA, and LGK974 (0.01–100 nM). Radioactive palmitate incorporation was quantified by scintillation counting to determine IC₅₀. [1]
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| Cell Assay |
STF3A-HEK293 cells (Wnt reporter) were treated with LGK974 (0.1–100 nM) for 24 hours ± Wnt3a-conditioned medium. Luciferase activity was measured to calculate EC₅₀. [1]
For proliferation assays, lung adenocarcinoma cells (e.g., H2030-BrM3) were plated and treated with LGK974 (0.001–10 μM). Cell viability was assessed at 72 hours using CellTiter-Glo. Wnt pathway inhibition was validated via qPCR for Axin2 and LEF1. [2] |
| Animal Protocol |
Dissolved 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
A murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30) MMTV-Wnt1 mice received oral LGK974 (3 mg/kg or 10 mg/kg) suspended in 0.5% methylcellulose/0.5% Tween-80, administered daily by gavage. Tumor volume was measured by caliper. [1] Lung adenocarcinoma PDX models were established in NSG mice. Mice were orally dosed with LGK974 (20 mg/kg in 0.5% methylcellulose/0.5% Tween-80) daily for 28 days. Tumor growth was monitored by caliper. [2] |
| References | |
| Additional Infomation |
LGK974 is a first-in-class PORCN inhibitor that blocks Wnt ligand secretion, thereby suppressing Wnt/β-catenin signaling in Wnt-addicted cancers. [1]
In lung adenocarcinoma, tumor progression is driven by Wnt-producing stromal niches. LGK974 abrogates this paracrine signaling, demonstrating therapeutic potential against stromal-dependent malignancies. [2] LGK974 is a carboxamide, the structure of which is that of acetamide substituted on carbon by a 2',3-dimethyl-2,4'-bipyridin-5-yl group and on nitrogen by a 5-(pyrazin-2-yl)pyridin-2-yl group. It is a highly potent, selective and orally bioavailable Porcupine inhibitor (a Wnt signalling inhibitor). It has a role as a Wnt signalling inhibitor. It is a member of bipyridines, a member of pyrazines, a member of pyridines and a secondary carboxamide. It is functionally related to an acetamide. WNT974 has been used in trials studying the treatment of Metastatic Colorectal Cancer and Squamous Cell Carcinoma, Head And Neck. Porcupine Inhibitor WNT974 is an orally available inhibitor of porcupine (PORCN), with potential antineoplastic activity. Upon oral administration, WNT974 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. Porcupine, a membrane-bound O-acyltransferase (MBOAT), is required for the palmitoylation of Wnt ligands, and plays a key role in Wnt ligand secretion and activity. Wnt signaling is dysregulated in a variety of cancers. |
| Molecular Formula |
C23H20N6O
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|---|---|
| Molecular Weight |
396.4445
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| Exact Mass |
396.169
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| Elemental Analysis |
C, 69.68; H, 5.08; N, 21.20; O, 4.04
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| CAS # |
1243244-14-5
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| Related CAS # |
2375595-49-4 (2HCl);1243244-14-5;
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| PubChem CID |
46926973
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| Appearance |
White to light brown solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
650.9±55.0 °C at 760 mmHg
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| Flash Point |
347.5±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.652
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| LogP |
2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
560
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C([H])([H])C1=C([H])N=C(C2C([H])=C([H])N=C(C([H])([H])[H])C=2[H])C(C([H])([H])[H])=C1[H])N([H])C1C([H])=C([H])C(C2C([H])=NC([H])=C([H])N=2)=C([H])N=1
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| InChi Key |
XXYGTCZJJLTAGH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H20N6O/c1-15-9-17(12-28-23(15)18-5-6-25-16(2)10-18)11-22(30)29-21-4-3-19(13-27-21)20-14-24-7-8-26-20/h3-10,12-14H,11H2,1-2H3,(H,27,29,30)
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| Chemical Name |
2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide
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| Synonyms |
NVP-LGK974; NVPLGK974; 1243244-14-5; 2-(2',3-Dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide; CHEBI:78030; NVP LGK974; LGK974; LGK-974; LGK 974; WNT974; WNT 974; WNT-974
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.31 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.31 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 2% DMSO+corn oil:5 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5224 mL | 12.6122 mL | 25.2245 mL | |
| 5 mM | 0.5045 mL | 2.5224 mL | 5.0449 mL | |
| 10 mM | 0.2522 mL | 1.2612 mL | 2.5224 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 LGK974 inhibits tumor growth ofRNF43-mutant pancreatic tumors in vivo.Proc Natl Acad Sci U S A.2013Jul 30;110(31):12649-54. |
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 LGK974 specifically inhibits the growth of pancreatic cancer cell lines harboringRNF43mutation.Proc Natl Acad Sci U S A.2013Jul 30;110(31):12649-54. |
 Characterization ofRNF43mutations in pancreatic cancer.Proc Natl Acad Sci U S A.2013Jul 30;110(31):12649-54. |
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