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LGK974 (WNT974) PORCN inhibitor

Name: LGK974 (WNT974)
SKU: S7143
Availability: InStock
Rating: 5 (91 reviews)

Cat.No.S7143

LGK974 (WNT974) is a potent and specific PORCN inhibitor that inhibits Wnt signaling with an IC50 of 0.4 nM in TM3 cells, and is currently in Phase 1.

Chemical Structure

Molecular Weight: 396.44

Jump to Mechanism of Action Cell Culture & Working Concentration Solubility Chemical Information, Storage & Stability Specificity

Quality Control

Batch: Purity: 99.98%

99.98

Products Often Used Together with LGK974 (WNT974)

Pictilisib (GDC-0941)

When combined with GDC-0941, it exhibits a synergistic effect in MDA-MB-231 cells.

AZD8055

Combination use of this compound and AZD-8055 reduces tumorigenesis and the immunosuppressive effects of early-stage myeloid-derived suppressor cells (eMDSCs) in mice.

Related Targets	JAK STAT TGF-beta/Smad Wnt/beta-catenin ERK GSK-3 Casein Kinase Notch ROCK Hedgehog/Smoothened PKA Secretase OCT KLF Stemness kinase SFRP Fascin
Related Products	Wnt-C59 (C59) IWP-L6 ETC-159 IWP-O1 GNF-6231

Cell Culture, Treatment & Working Concentration

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

Chemical Information, Storage & Stability

Molecular Weight	396.44	Formula	C₂₃H₂₀N₆O	Storage (From the date of receipt)	3 years-20°Cpowder
CAS No.	1243244-14-5	Download SDF		Storage of Stock Solutions	1 year-80°Cin solvent 1 month-20°Cin solvent
Synonyms	NVP-LGK974, WNT974			Smiles	CC1=CC(=CN=C1C2=CC(=NC=C2)C)CC(=O)NC3=NC=C(C=C3)C4=NC=CN=C4

Solubility

In vitro
Batch:

DMSO : 79 mg/mL (199.27 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
=	×	×

Dilution Calculator Molecular Weight Calculator

In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	5%DMSO 1 Corn oil Validated by Selleck labs. Should you need adjustments to this formulation, contact our sales team for custom testing.	1.350mg/ml (3.41mM)	Taking the 1 mL working solution as an example, add 50 μL of 27 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

Dosage: mg/kg Average weight of animals: g Dosing volume per animal:μL Number of animals:

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Mechanism of Action

Features	Orally bioavailable Porcupine-specific inhibitor that has been tested in Phase I clinical trials for treatment of malignancies dependent on Wnt ligands.
Targets/IC₅₀/Ki	Porcn ^[1] (TM3 cells)
In vitro	In the PORCN radioligand binding assay, LGK974 (WNT974) effectively displaces [³H]-GNF-1331 with an IC50 of 1 nM and shows no major cytotoxicity in cells up to 20 µM. It 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] This compound specifically inhibits the growth of three RNF43-mutant cell lines, HPAF-II, PaTu 8988S, and Capan-2. ^[2]
In vivo	In a murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30), LGK974 (WNT974) (3 mg/kg) inhibits Wnt signaling in vivo and induces tumor regression without significant body weight loss in the mice. ^[1] This compound (5 mg/kg, p.o., BID) also inhibits tumor growth of RNF43-mutant pancreatic tumors (HPAF-II and Capan-2) in vivo. ^[2]
References	[1] https://pubmed.ncbi.nlm.nih.gov/24277854/ [2] https://pubmed.ncbi.nlm.nih.gov/23847203/

Applications

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

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

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

Tech Support

Handling Instructions

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Frequently Asked Questions

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

Answer:
It is a lipophilic compound.

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