LGK-974

別名: NVP-LGK974, WNT974

目錄號(hào)：S7143 Purity: 99.98%

LGK-974 (NVP-LGK974, WNT974)是一種有效的特異性PORCN抑制劑,抑制Wnt信號(hào)通路，在TM3細(xì)胞中IC50為0.4 nM。Phase 1。

LGK-974 Chemical Structure

CAS: 1243244-14-5

規(guī)格	價(jià)格	庫存
10mM (1mL in DMSO)	2022.93	現(xiàn)貨
5mg	2019.87	現(xiàn)貨
50mg	7962.02	現(xiàn)貨
1g	48894.52	現(xiàn)貨
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產(chǎn)品質(zhì)控

批次：純度： 99.98%

99.98

常與LGK-974一起在實(shí)驗(yàn)中被使用的化合物

Pictilisib (GDC-0941)

LGK-974和GDC-0941聯(lián)合使用在MDA-MB-231細(xì)胞中表現(xiàn)出協(xié)同作用。

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

Vismodegib (GDC-0449)

LGK-974和GDC-0449聯(lián)合使用可顯著降低小鼠基底細(xì)胞癌(BCC)模型中的腫瘤負(fù)荷，比單獨(dú)使用任一抑制劑更有效。

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

AZD8055

LGK-974和AZD-8055聯(lián)合使用可減少小鼠中的腫瘤發(fā)生和早期骨髓源性抑制細(xì)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聯(lián)合使用可有效減少PDCs異種移植小鼠模型中的腫瘤生長(zhǎng)，并增加腫瘤對(duì)5-FU的敏感性。

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

Chloroquine

LGK-974和Chloroquine聯(lián)合使用可協(xié)同抑制RNF43突變型PDAC細(xì)胞系A(chǔ)sPC-1/HPAF-II的生長(zhǎng)。

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

LGK-974相關(guān)產(chǎn)品

相關(guān)產(chǎn)品	Wnt-C59 (C59) IWP-L6 ETC-159 IWP-O1	點(diǎn)擊展開
相關(guān)化合物庫	激酶抑制劑庫 FDA藥物庫干細(xì)胞小分子化合物庫 GPCR小分子化合物庫干細(xì)胞分化化合物庫	點(diǎn)擊展開

細(xì)胞實(shí)驗(yàn)數(shù)據(jù)示例

細(xì)胞系	實(shí)驗(yàn)類型	給藥濃度	孵育時(shí)間	活性描述	文獻(xiàn)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
點(diǎn)擊查看更多細(xì)胞系數(shù)據(jù)

生物活性

產(chǎn)品描述

LGK-974 (NVP-LGK974, WNT974)是一種有效的特異性PORCN抑制劑,抑制Wnt信號(hào)通路，在TM3細(xì)胞中IC50為0.4 nM。Phase 1。

特性

LGK-974是口服有效的Porcupine-特異性抑制劑，用于治療依賴Wnt配體的惡性腫瘤，目前處于I期臨床試驗(yàn)階段。

靶點(diǎn)

Porcn ^[1]
(TM3 cells)

體外研究(In Vitro)
體外研究活性	LGK-974在PORCN放射配體結(jié)合測(cè)定中，可有效取代[³H]GNF -1331，IC50為1 nM，在細(xì)胞中達(dá)到20μM時(shí)也沒有很大的細(xì)胞毒作用。LGK974抑制所有測(cè)試的Wnts，IC50為0.05到2.4 nM，這與PORCN表型的基因缺失一致。^[1] LGK974能特異性地抑制三種RNF43突變細(xì)胞株HPAF-II, PaTu 8988S, 和 Capan-2的生長(zhǎng)。^[2]
細(xì)胞實(shí)驗(yàn)	細(xì)胞系	HPAF-II, PaTu 8988S, 和 Capan-2 細(xì)胞
	濃度	~1 μM
	孵育時(shí)間	3 天
	方法	細(xì)胞以每份密度6,000–12,000個(gè)接種在96孔板上，加入 DMSO或1 μM LGK974的培養(yǎng)基培養(yǎng)。3天后，加入新鮮的含有20 μM EdU的培養(yǎng)液，EdU來自Click-iT EdU Alexa Fluor 488 HCS試劑盒，孔板在37°C含有5% CO₂的濕潤(rùn)空氣溫育2小時(shí)。用4% (mass/vol) paraformaldehyde固定細(xì)胞30分鐘，用PBS清洗，滲透，然后用50 μg/mL溶于PBS的Hoechst 染色30分鐘。清洗后，根據(jù)Click-iT EdU試劑盒的說明檢測(cè)。在每種條件下每孔進(jìn)行一式三份。
實(shí)驗(yàn)圖片	檢測(cè)方法	檢測(cè)指標(biāo)	實(shí)驗(yàn)圖片	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

體內(nèi)研究(In Vivo)
體內(nèi)研究活性	LGK-974 (3 mg/kg)作用于小鼠MMTV-WNT1腫瘤模型和人的頭部和頸部鱗狀細(xì)胞癌模型（hn30），抑制 Wnt 信號(hào)通路，誘導(dǎo)腫瘤退化且小鼠體重沒有明顯的下降。^[1] LGK-974 (5 mg/kg, p.o., BID) 也能抑制RNF43-突變胰腺腫瘤(HPAF-II 和Capan-2)的生長(zhǎng)。^[2]
動(dòng)物實(shí)驗(yàn)	Animal Models	小鼠MMTV-Wnt1腫瘤模型和人體頭頸部鱗狀細(xì)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
臨床試驗(yàn)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

參考文獻(xiàn)
[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.

參考文獻(xiàn)

[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.