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LGK-974

Name: LGK-974
Brand: Selleck Chemicals
SKU: S7143
Rating: 5 (89 reviews)

Synonyms: NVP-LGK974, WNT974

Catalog No.S7143 Purity:99.98%

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

CAS No. 1243244-14-5

Purity & Quality Control

Batch: Purity: 99.98%

99.98

Products often used together with LGK-974

Pictilisib (GDC-0941)

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

Tzeng HE, et al. Oncotarget. 2015 May 10;6(13):11061-73.

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.

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

References

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)	3 years-20°Cpowder	Storage of Stock Solutions Aliquot the stock solutions to avoid repeated freeze-thaw cycles	1 year-80°Cin solvent
Storage (From the date of receipt)	3 years-20°Cpowder		1 month-20°Cin solvent

In vitro
Batch:

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

Water : Insoluble

Ethanol : Insoluble

Molecular Weight Calculator

In vivo Batch: Add solvents to the product individually and in order.				In vivo Formulation Calculator
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.

Preparing Stock Solutions

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
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Dilution Calculator Molecular Weight Calculator

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.

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

Tel: +1-832-582-8158 Ext:3
If you have any other enquiries, please leave a message.

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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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