Home Stem Cells & Wnt PORCN inhibitor LGK-974 For research use only.

LGK-974

Synonyms: NVP-LGK974, WNT974

LGK-974 (NVP-LGK974, WNT974) is a potent and specific PORCN inhibitor, and inhibits Wnt signaling with IC50 of 0.4 nM in TM3 cells. Phase 1.

LGK-974 Chemical Structure

LGK-974 Chemical Structure

CAS No. 1243244-14-5

Purity & Quality Control

Products often used together with LGK-974

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LGK-974 and GDC-0941combined use exhibits synergistic effect in MDA-MB-231 cells.

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AZD8055

LGK-974 and AZD-8055 combination use reduces tumorigenesis and the immunosuppressive effects of early-stage myeloid-derived suppressor cells (eMDSCs) in mice.

Zhang W, et al. J Leukoc Biol. 2023 May 2;113(5):445-460.

LGK-974 Related Products

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
HPAF-II  Growth Inhibition Assay 1 μM  DMSO inhibits the growth of pancreatic cancer cell lines with RNF43mutation  23847203
PaTu 8988S  Growth Inhibition Assay 1 μM  DMSO inhibits the growth of pancreatic cancer cell lines with RNF43mutation  23847203
Capan-2 Growth Inhibition Assay 1 μM  DMSO inhibits the growth of pancreatic cancer cell lines with RNF43 mutation 23847203
HPAF-II Growth Inhibition Assay 1 μM  DMSO inhibits the growth of pancreatic cancer cell lines with RNF43 mutation 23847203
PaTu8988S Growth Inhibition Assay 1 μM  DMSO inhibits the growth of pancreatic cancer cell lines with RNF43 mutation 23847203
293T  Function Assay IC50 of 0.4 nM to inhibits Wnt signaling in the aforementioned Wnt coculture assay 24277854
293T  Function Assay IC50 of 1 nM to compete off [3H]-GNF-1331 in a dose-dependent manner 24277854
HT1080 Function assay Inhibition of porcupine activity (unknown origin) expressed in human HT1080 cells assessed as suppression of Wnt3A-mediated super top flash activity by STF luciferase assay, IC50 = 0.0004 μM. 26522946
L Wnt3A, HEK293 Function assay 48 hrs Inhibition of Wnt signaling (unknown origin) expressed in mouse L Wnt3A cells co-cultured with HEK293 cells after 48 hrs by Super-top flash reporter gene assay, IC50 = 0.0009 μM. 26647303
L Wnt3A, HEK293 Function assay 48 hrs Inhibition of porcupine in mouse L Wnt3A cells co-cultured with HEK293 cells after 48 hrs by Super-top flash reporter gene assay, IC50 = 0.0009 μM. 27692509
L Wnt3A, HEK293 Function assay 48 hrs Inhibition of porcupine in mouse L Wnt3A cells co-cultured with HEK293 cells assessed as suppression of Wnt signaling after 48 hrs by Super-top flash reporter gene assay, IC50 = 0.0009 μM. 29499483
HEK293T Function assay 0.1 uM 48 hrs Inhibition of porcupine (unknown origin) in HEK293T cells transfected with pLibin-WNT3A plasmid assessed as reduction in Wnt3A secretion into cell culture medium at 0.1 uM after 48 hrs by Western blot technique 26647303
HEK293T Function assay 0.1 uM 48 hrs Inhibition of porcupine in HEK293T cells transfected with pLibin-WNT3A plasmid assessed as reduction in Wnt3A secretion into cell culture medium at 0.1 uM after 48 hrs by Western blot method 27692509
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells 29435139
HEK293 Function assay 100 nM 48 hrs Inhibition of porcupine in HEK293 cells transfected with pLibin-WNT3A plasmid assessed as downregulation of LRP6 phosphorylation at 100 nM after 48 hrs by Western blot analysis 29499483
HEK293T Function assay 100 nM 48 hrs Inhibition of porcupine in HEK293T cells transfected with pLibin-WNT3A plasmid assessed as reduction in Wnt3A secretion into cell culture medium at 100 nM after 48 hrs by Western blot method 29499483
PA1 Function assay 24 hrs Inhibition of porcupine-mediated Wnt/beta-catenin signaling in human PA1 cells assessed as downregulation of Axin2 mRNA expression after 24 hrs by real-time PCR analysis 29499483
HEK293 Function assay 100 nM 48 hrs Inhibition of porcupine in HEK293 cells transfected with pLibin-WNT3A plasmid assessed as downregulation of disheveled 2 phosphorylation at 100 nM after 48 hrs by Western blot analysis 29499483
Click to View More Cell Line Experimental Data

Biological Activity

Description LGK-974 (NVP-LGK974, WNT974) is a potent and specific PORCN inhibitor, and inhibits Wnt signaling with IC50 of 0.4 nM in TM3 cells. Phase 1.
Features Orally bioavailable Porcupine-specific inhibitor that has been tested in Phase I clinical trials for treatment of malignancies dependent on Wnt ligands.
Targets
Porcn [1]
(TM3 cells)
In vitro
In vitro 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. [1] LGK974 specifically inhibits the growth of three RNF43-mutant cell lines, HPAF-II, PaTu 8988S, and Capan-2. [2]
Cell Research Cell lines HPAF-II, PaTu 8988S, and Capan-2 cells
Concentrations ~1 μM
Incubation Time 3 days
Method

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.
Experimental Result Images Methods Biomarkers Images PMID
Western blot p-LRP6 / Axin / p-GSK3β / p-β-catenin / β-catenin NF-κB / IκB / p-IκB Nrf2 / Wnt3A / HO-1 / NQO-1 / Survivin 28128299
Immunofluorescence beta-catenin FUT8 α1, 6-fucosylation 25639201
In Vivo
In vivo In 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. [1] LGK974 (5 mg/kg, p.o., BID) also inhibits tumor growth of RNF43-mutant pancreatic tumors (HPAF-II and Capan-2) in vivo. [2]
Animal Research Animal Models A murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30)
Dosages ~3 mg/kg daily
Administration Oral gavage
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01351103 Active not recruiting
Pancreatic Cancer|BRAF Mutant Colorectal Cancer|Melanoma|Triple Negative Breast Cancer|Head and Neck Squamous Cell Cancer|Cervical Squamous Cell Cancer|Esophageal Squamous Cell Cancer|Lung Squamous Cell Cancer
Novartis Pharmaceuticals|Novartis
 December 1 2011 Phase 1

Chemical Information & Solubility

Molecular Weight 396.44 Formula

C23H20N6O
CAS No. 1243244-14-5 SDF Download LGK-974 SDF
Smiles CC1=CC(=CN=C1C2=CC(=NC=C2)C)CC(=O)NC3=NC=C(C=C3)C4=NC=CN=C4
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 79 mg/mL ( (199.27 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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In vivo
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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Frequently Asked Questions

Question 1:
If LGK974 is a lipophilic or hydrophilic substance?

Answer:
LGK974 is a lipophilic compound.

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