LGK-974

别名: NVP-LGK974, WNT974

LGK-974 (NVP-LGK974, WNT974)是一种有效的特异性PORCN抑制剂,抑制Wnt信号通路,在TM3细胞中IC50为0.4 nM。Phase 1。

LGK-974 Chemical Structure

LGK-974 Chemical Structure

CAS: 1243244-14-5

规格 价格 库存 购买数量
10mM (1mL in DMSO) RMB 2022.93 现货
5mg RMB 2019.87 现货
50mg RMB 7962.02 现货
1g RMB 48894.52 现货
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客户使用Selleck的LGK-974发表文献79

产品质控

批次: 纯度: 99.98%
99.50

常与LGK-974一起在实验中被使用的化合物

Pictilisib (GDC-0941)


LGK-974和GDC-0941联合使用在MDA-MB-231细胞中表现出协同作用。

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

Vismodegib (GDC-0449)


LGK-974和GDC-0449联合使用可显着降低小鼠基底细胞癌(BCC)模型中的肿瘤负荷,比单独使用任一抑制剂更有效。

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

AZD8055


LGK-974和AZD-8055联合使用可减少小鼠中的肿瘤发生和早期骨髓源性抑制细胞(eMDSC)的免疫抑制作用。

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

5-FU (5-Fluorouracil)


LGK-974和5-FU联合使用可有效减少PDCs异种移植小鼠模型中的肿瘤生长,并增加肿瘤对5-FU的敏感性。

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

Chloroquine


LGK-974和Chloroquine联合使用可协同抑制RNF43突变型PDAC细胞系AsPC-1/HPAF-II的生长。

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

LGK-974相关产品

PORCN抑制剂选择性比较

细胞实验数据示例

细胞系 实验类型 给药浓度 孵育时间 活性描述 文献信息
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
点击查看更多细胞系数据

生物活性

产品描述 LGK-974 (NVP-LGK974, WNT974)是一种有效的特异性PORCN抑制剂,抑制Wnt信号通路,在TM3细胞中IC50为0.4 nM。Phase 1。
特性 LGK-974是口服有效的Porcupine-特异性抑制剂,用于治疗依赖Wnt配体的恶性肿瘤,目前处于I期临床试验阶段。
靶点
Porcn [1]
(TM3 cells)
体外研究(In Vitro)
体外研究活性 LGK-974在PORCN放射配体结合测定中,可有效取代[3H]GNF -1331,IC50为1 nM,在细胞中达到20µM时也没有很大的细胞毒作用。LGK974抑制所有测试的Wnts,IC50为0.05到2.4 nM,这与PORCN表型的基因缺失一致。[1] LGK974能特异性地抑制三种RNF43突变细胞株HPAF-II, PaTu 8988S, 和 Capan-2的生长。[2]
细胞实验 细胞系 HPAF-II, PaTu 8988S, 和 Capan-2 细胞
浓度 ~1 μM
孵育时间 3 天
方法 细胞以每份密度6,000–12,000个接种在96孔板上,加入 DMSO或1 μM LGK974的培养基培养。3天后,加入新鲜的含有20 μM EdU的培养液,EdU来自Click-iT EdU Alexa Fluor 488 HCS试剂盒,孔板在37°C含有5% CO2的湿润空气温育2小时。用4% (mass/vol) paraformaldehyde固定细胞30分钟,用PBS清洗,渗透,然后用50 μg/mL溶于PBS的Hoechst 染色30分钟。清洗后,根据Click-iT EdU试剂盒的说明检测。在每种条件下每孔进行一式三份。
实验图片 检测方法 检测指标 实验图片 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
体内研究(In Vivo)
体内研究活性 LGK-974 (3 mg/kg)作用于小鼠MMTV-WNT1肿瘤模型和人的头部和颈部鳞状细胞癌模型(hn30),抑制 Wnt 信号通路,诱导肿瘤退化且小鼠体重没有明显的下降。[1] LGK-974 (5 mg/kg, p.o., BID) 也能抑制RNF43-突变胰腺肿瘤(HPAF-II 和Capan-2)的生长。[2]
动物实验 Animal Models 小鼠MMTV-Wnt1肿瘤模型和人体头颈部鳞状细胞癌模型(HN30)
Dosages ~3 mg/kg 每天
Administration 口服灌胃
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

化学信息&溶解度

分子量 396.44 分子式

C23H20N6O

CAS号 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
储存条件(自收到货起)

体外溶解度
批次:

DMSO : 79 mg/mL ( 199.27 mM; DMSO吸湿会降低化合物溶解度,请使用新开封DMSO)

Water : Insoluble

Ethanol : Insoluble

摩尔浓度计算器

体内溶解度
批次:

现配现用,请按从左到右的顺序依次添加,澄清后再加入下一溶剂

动物体内配方计算器

实验计算

摩尔浓度计算器

质量 浓度 体积 分子量

动物体内配方计算器(澄清溶液)

第一步:请输入基本实验信息(考虑到实验过程中的损耗,建议多配一只动物的药量)

mg/kg g μL

第二步:请输入动物体内配方组成(配方适用于不溶于水的药物;不同批次药物配方比例不同,请联系Selleck为您提供正确的澄清溶液配方)

% DMSO % % Tween 80 % ddH2O
%DMSO %

计算结果:

工作液浓度: mg/ml;

DMSO母液配制方法: mg 药物溶于μL DMSO溶液(母液浓度mg/mL,:如该浓度超过该批次药物DMSO溶解度,请先联系Selleck);

体内配方配制方法:μL DMSO母液,加入μL PEG300,混匀澄清后加入μL Tween 80,混匀澄清后加入μL ddH2O,混匀澄清。

体内配方配制方法:μL DMSO母液,加入μL Corn oil,混匀澄清。

注意:1. 首先保证母液是澄清的;
2.一定要按照顺序依次将溶剂加入,进行下一步操作之前必须保证上一步操作得到的是澄清的溶液,可采用涡旋、超声或水浴加热等物理方法助溶。

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常见问题及建议解决方法

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

回答:
LGK974 is a lipophilic compound.

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