LGK-974

別名：NVP-LGK974, WNT974

製品コード：S7143 純度：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.

CAS No. 1243244-14-5

サイズ	価格(税別)	在庫状況
10mM (1mL in DMSO)	JPY 44500	国内在庫あり
5mg	JPY 37000	国内在庫あり
50mg	JPY 145500	国内在庫あり
1g	JPY 895500	国内在庫なし(納期7~10日)

代表番号: 045-509-1970\|電子メール：[email protected] よく尋ねられる質問

文献中Selleckの製品使用例（79）

製品安全説明書

現在のバッチを見る：純度： 99.98%

99.98

LGK-974と併用されることが多い化合物

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.

Vismodegib (GDC-0449)

LGK-974 and GDC-0449 combination use strongly decreases tumor burden in a murine basal cell carcinoma (BCC) model much more efficiently than either inhibitor's alone.

Peer E, et al. Cancers (Basel). 2019 Apr 15;11(4):538.

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.

5-FU (5-Fluorouracil)

LGK-974 and 5-FU combination use effectively reduces tumor growth, and increases the sensitivity of the tumors to 5-FU in patient-derived tumor cells (PDCs) xenograft mouse model.

Cho YH, et al. Nature communications 11.1 (2020): 5321.

Chloroquine

LGK-974 and chloroquine combination use synergistically inhibits the growth of RNF43-mutant PDAC cell lines AsPC-1/HPAF-II.

Aguilera KY, et al. Mol Cancer Ther. 2022 Jun 1;21(6):936-947.

LGK-974関連製品

関連製品	Wnt-C59 (C59) IWP-L6 ETC-159 IWP-O1	もっと見る
関連化合物ライブラリー	Kinase Inhibitor Library FDA-approved Drug Library Stem Cell Signaling Compound Library GPCR Compound Library Stem Cell Differentiation Compound Library	もっと見る

PORCN阻害剤の選択性比較

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	活性情報	PMID
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
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
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
PaTu8988S	Growth Inhibition Assay	1 μM		inhibits the growth of pancreatic cancer cell lines with RNF43 mutation	23847203
HPAF-II	Growth Inhibition Assay	1 μM		inhibits the growth of pancreatic cancer cell lines with RNF43 mutation	23847203
Capan-2	Growth Inhibition Assay	1 μM		inhibits the growth of pancreatic cancer cell lines with RNF43 mutation	23847203
PaTu 8988S	Growth Inhibition Assay	1 μM		inhibits the growth of pancreatic cancer cell lines with RNF43mutation	23847203
HPAF-II	Growth Inhibition Assay	1 μM		inhibits the growth of pancreatic cancer cell lines with RNF43mutation	23847203
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
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
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
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
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生物活性

製品説明

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.

特性

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]
細胞実験	細胞株	HPAF-II, PaTu 8988S, and Capan-2 cells
	濃度	~1 μM
	反応時間	3 days
	実験の流れ	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.
実験結果図	Methods	Biomarkers	結果図	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]
動物実験	動物モデル	A murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30)
	投与量	~3 mg/kg daily
	投与経路	Oral gavage

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試験 (data from https://clinicaltrials.gov, updated on 2024-01-11)
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

参考
[1] Liu J, et al. Proc Natl Acad Sci U S A. 2013, 110(50), 20224-20229. [2] Jiang X, et al. Proc Natl Acad Sci U S A. 2013, 110(31), 12649-12654.

参考

化学情報

分子量	396.44	化学式	C₂₃H₂₀N₆O
CAS No.	1243244-14-5	SDF	Download LGK-974 SDFをダウンロードする
Smiles	CC1=CC(=CN=C1C2=CC(=NC=C2)C)CC(=O)NC3=NC=C(C=C3)C4=NC=CN=C4
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1年-80°Cin solvent
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1个月-20°Cin solvent

In vitro
Batch:

DMSO : 79 mg/mL ( (199.27 mM)； Warmed with 50℃ water bath; 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Water : Insoluble

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量	濃度	体積	分子量
=	×	×

希釈計算器分子量計算器

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

投与量 mg/kg 動物平均体重 g 投与体積（動物毎）μL 動物数匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH₂O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

技術サポート

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Handling Instructions

他に質問がある場合は、お気軽にお問い合わせください。

* 必須

よくある質問（FAQ）

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

回答
LGK974 is a lipophilic compound.

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