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LGK-974
別名: NVP-LGK974, WNT974
LGK-974 (NVP-LGK974, WNT974)是一種有效的特異性PORCN抑制劑,抑制Wnt信號通路，在TM3細胞中IC50為0.4 nM。Phase 1。
LGK-974 Chemical Structure
CAS: 1243244-14-5
產(chǎn)品質(zhì)控
批次：
純度：
99.98%
99.98
常與LGK-974一起在實驗中被使用的化合物
LGK-974和GDC-0941聯(lián)合使用在MDA-MB-231細胞中表現(xiàn)出協(xié)同作用。
LGK-974和GDC-0449聯(lián)合使用可顯著降低小鼠基底細胞癌(BCC)模型中的腫瘤負荷，比單獨使用任一抑制劑更有效。
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胞(eMDSC)的免疫抑制作用。
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，并增加腫瘤對5-FU的敏感性。
LGK-974和Chloroquine聯(lián)合使用可協(xié)同抑制RNF43突變型PDAC細胞系A(chǔ)sPC-1/HPAF-II的生長。
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 | 點擊展開 |
|---|---|---|
| 相關(guān)化合物庫 | 激酶抑制劑庫 FDA藥物庫 干細胞小分子化合物庫 GPCR小分子化合物庫 干細胞分化化合物庫 | 點擊展開 |
細胞實驗數(shù)據(jù)示例
| 細胞系 | 實驗類型 | 給藥濃度 | 孵育時間 | 活性描述 | 文獻信息 |
|---|---|---|---|---|---|
| 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 | ||
| 點擊查看更多細胞系數(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信號通路，在TM3細胞中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期臨床試驗階段。 | |
| 靶點 |
|
| 體外研究(In Vitro) | ||||
| 體外研究活性 | LGK-974在PORCN放射配體結(jié)合測定中，可有效取代[3H]GNF -1331，IC50為1 nM，在細胞中達到20μM時也沒有很大的細胞毒作用。LGK974抑制所有測試的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突變細胞株HPAF-II, PaTu 8988S, 和 Capan-2的生長。[2] | |||
|---|---|---|---|---|
| 細胞實驗 | 細胞系 | HPAF-II, PaTu 8988S, 和 Capan-2 細胞 | ||
| 濃度 | ~1 μM | |||
| 孵育時間 | 3 天 | |||
| 方法 | 細胞以每份密度6,000–12,000個接種在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的濕潤空氣溫育2小時。用4% (mass/vol) paraformaldehyde固定細胞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。在每種條件下每孔進行一式三份。 | |||
| 實驗圖片 | 檢測方法 | 檢測指標 | 實驗圖片 | 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胞癌模型（hn30），抑制 Wnt 信號通路，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。[2] | |
|---|---|---|
| 動物實驗 | Animal Models | 小鼠MMTV-Wnt1腫瘤模型和人體頭頸部鱗狀細胞癌模型(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 |
化學(xué)信息&溶解度
| 分子量 | 396.44 | 分子式 | C23H20N6O |
| CAS號 | 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 | ||
| 儲存條件(自收到貨起) | |||
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體外溶解度 |
DMSO : 79 mg/mL ( (199.27 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO) Water : Insoluble Ethanol : Insoluble |
摩爾濃度計算器 |
|
體內(nèi)溶解度 現(xiàn)配現(xiàn)用，請按從左到右的順序依次添加，澄清后再加入下一溶劑 |
動物體內(nèi)配方計算器 | ||||
實驗計算
動物體內(nèi)配方計算器（澄清溶液）
第一步：請輸入基本實驗信息（考慮到實驗過程中的損耗，建議多配一只動物的藥量）
mg/kg
g
μL
只
第二步：請輸入動物體內(nèi)配方組成（配方適用于不溶于水的藥物；不同批次藥物配方比例不同，請聯(lián)系Selleck為您提供正確的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
計算結(jié)果：
工作液濃度： mg/ml；
DMSO母液配制方法： mg 藥物溶于μL DMSO溶液（母液濃度mg/mL，注：如該濃度超過該批次藥物DMSO溶解度，請先聯(lián)系Selleck）；
體內(nèi)配方配制方法：取μL DMSO母液，加入μL PEG300，混勻澄清后加入μL Tween 80，混勻澄清后加入μL ddH2O，混勻澄清。
體內(nèi)配方配制方法：取μL DMSO母液，加入μL Corn oil，混勻澄清。
注意：1. 首先保證母液是澄清的；
2.一定要按照順序依次將溶劑加入，進行下一步操作之前必須保證上一步操作得到的是澄清的溶液，可采用渦旋、超聲或水浴加熱等物理方法助溶。
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常見問題及建議解決方法
問題 1:
If LGK974 is a lipophilic or hydrophilic substance?
回答：
LGK974 is a lipophilic compound.
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