LGK-974PORCN inhibitor,potent and specific CAS# 1243244-14-5 |
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Quality Control & MSDS
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| Cas No. | 1243244-14-5 | SDF | Download SDF |
| PubChem ID | 46926973 | Appearance | Powder |
| Formula | C23H20N6O | M.Wt | 396.44 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 32 mg/mL (80.72 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 2-[5-methyl-6-(2-methylpyridin-4-yl)pyridin-3-yl]-N-(5-pyrazin-2-ylpyridin-2-yl)acetamide | ||
| SMILES | CC1=C(N=CC(=C1)CC(=O)NC2=NC=C(C=C2)C3=NC=CN=C3)C4=CC(=NC=C4)C | ||
| Standard InChIKey | XXYGTCZJJLTAGH-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C23H20N6O/c1-15-9-17(12-28-23(15)18-5-6-25-16(2)10-18)11-22(30)29-21-4-3-19(13-27-21)20-14-24-7-8-26-20/h3-10,12-14H,11H2,1-2H3,(H,27,29,30) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | LGK-974 is a potent and specific inhibitor of PORCN. | |||||
| Targets | PORCN | |||||
LGK-974 Dilution Calculator
LGK-974 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.5224 mL | 12.6122 mL | 25.2245 mL | 50.449 mL | 63.0612 mL |
| 5 mM | 0.5045 mL | 2.5224 mL | 5.0449 mL | 10.0898 mL | 12.6122 mL |
| 10 mM | 0.2522 mL | 1.2612 mL | 2.5224 mL | 5.0449 mL | 6.3061 mL |
| 50 mM | 0.0504 mL | 0.2522 mL | 0.5045 mL | 1.009 mL | 1.2612 mL |
| 100 mM | 0.0252 mL | 0.1261 mL | 0.2522 mL | 0.5045 mL | 0.6306 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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LGK-974 is a potent and specific small-molecule inhibitor of Porcupine (PORCN) with IC50 value of 1nM [1].
LGK-974 is discovered as a highly specific and potent PORCN inhibitor. Even 20μM LGK974 shows no significant cytotoxicity in cells. LGK-974 inhibits Wnt signaling in the Wnt co-culture assay with an IC50 of 0.4nM. It can block the PORCN-dependent Wnt secretion in a dose-dependent manner. In MMTV-Wnt1 tumor model, LGK-974 induces significant tumor regression through affecting the Wnt signaling events. It inhibits both AXIN2 expression and phospho-LRP6 (pLRP6) levels. It is proved that LGK974 promotes tumor regressions at doses that spare normal tissues. Additionally, LGK-974 potently reduces Wnt-dependent AXIN2 mRNA levels in HN30 cells with IC50 value of 0.3nM and it strongly attenuates HN30 colony formation, partly through inhibiting the β-catenin–dependent activities. Moreover, the anti-tumor efficacy has also been found in the mouse model of Wnt-dependent human HNSCC cell Line [1].
References:
[1] Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Schuller AG, Li AG, Cheng D, Li J, Tompkins C, Pferdekamper A, Steffy A, Cheng J, Kowal C, Phung V, Guo G, Wang Y, Graham MP, Flynn S, Brenner JC, Li C, Villarroel MC, Schultz PG, Wu X, McNamara P, Sellers WR, Petruzzelli L, Boral AL, Seidel HM, McLaughlin ME, Che J, Carey TE, Vanasse G, Harris JL. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9.
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The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling.[Pubmed:28627706]
Int J Oncol. 2017 Aug;51(2):545-554.
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of antioxidant and detoxification activities that can eliminate reactive oxygen species (ROS) produced via irradiation. However, Nrf2 overexpression in liver cancer cells may cause both radioresistance and chemoresistance. Reducing Nrf2 levels can enhance the radiosensitivity of HepG2 cells. Wingless/int-3A (Wnt3A) is a Wnt family protein that mainly activates the canonical Wnt signaling pathway. Recent studies showed that the Axin1-GSK-3beta protein complex, a component of the canonical Wnt signaling pathway, can capture Nrf2 and facilitate its ubiquitination and proteasomal degradation in the cytoplasm. This protein complex is degraded upon activation of the Wnt signaling pathway. In the present study, we treated HepG2 cells with the Wnt3A inhibitor LGK-974, an effective and specific PORCN inhibitor that can prevent the formation of a proper folding of the Wnt protein in the endoplasmic reticulum. We found that HepG2 cells became more sensitive to radiation with increasing LGK-974 concentrations. Upon 2 Gy or 4 Gy irradiation, the cells treated with LGK-974 more frequently underwent apoptosis and grew less rapidly. PCR and western blot results showed that inhibiting the secretion of Wnt3A blocked the Wnt signaling pathway and prevented Nrf2 signaling. Notably, the Wnt inhibitor may serve as a radiosensitizing drug.
