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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
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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
临床试验信息 (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

参考文献
[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.

参考文献