LGK-974
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.
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 396.44 |
| Cas No. | 1243244-14-5 |
| Formula | C23H20N6O |
| Solubility | insoluble in H2O; ≥19.8 mg/mL in DMSO; ≥2.64 mg/mL in EtOH with gentle warming and ultrasonic |
| Chemical Name | 2-[5-methyl-6-(2-methylpyridin-4-yl)pyridin-3-yl]-N-(5-pyrazin-2-ylpyridin-2-yl)acetamide |
| SDF | Download SDF |
| Canonical SMILES | CC1=C(N=CC(=C1)CC(=O)NC2=NC=C(C=C2)C3=NC=CN=C3)C4=CC(=NC=C4)C |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment : | |
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Cell lines |
YAPC-STF cells, pancreatic cancer cells, HN30 cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
1 μM for 24-48 h |
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Applications |
LGK974 specifically blocked the growth of pancreatic cancer cell lines harboring RNF43 mutation. LGK974 increased the cell surface level of Frizzled and decreased the mRNA levels of AXIN2 and RNF43 [1]. Moreover, LGK974 inhibited Wnt signaling in HN30 cells with an IC50 value of 0.3 nM [2]. |
| Animal experiment : | |
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Animal models |
Mice bearing HPAF-II xenografts model, MMTV-Wnt1 tumor model |
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Dosage form |
5 mg/kg; oral gavage (p.o.) twice daily (BID) for 14 -35 days; or 0.3, 1.0, and 3.0 mg/kg per day for 13 d. |
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Applications |
Treatment of mice bearing HPAF-II xenografts with 5 mg/kg LGK974 resulted in significant inhibition of tumor growth. Furthermore, treatment of mice bearing Capan-2 xenografts with 5 mg/kg LGK974 achieved tumor stasis [1]. Moreover, LGK974 induced tumor regression by targeting Wnt signaling in a mechanistic MMTV-Wnt1 tumor model [2]. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: 1. Jiang, X., Hao, H. X., Growney, J. D., Woolfenden, S., Bottiglio, C., Ng, N., Lu, B., Hsieh, M. H., Bagdasarian, L., Meyer, R., Smith, T. R., Avello, M., Charlat, O., Xie, Y., Porter, J. A., Pan, S., Liu, J., McLaughlin, M. E. and Cong, F. (2013) Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A. 110, 12649-12654 2. Liu, J., Pan, S., Hsieh, M. H., Ng, N., Sun, F., Wang, T., Kasibhatla, S., Schuller, A. G., Li, A. G., Cheng, D., Li, J., Tompkins, C., Pferdekamper, A., Steffy, A., Cheng, J., Kowal, C., Phung, V., Guo, G., Wang, Y., Graham, M. P., Flynn, S., Brenner, J. C., Li, C., Villarroel, M. C., Schultz, P. G., Wu, X., McNamara, P., Sellers, W. R., Petruzzelli, L., Boral, A. L., Seidel, H. M., McLaughlin, M. E., Che, J., Carey, T. E., Vanasse, G. and Harris, J. L. (2013) Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 110, 20224-20229 |
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| Description | LGK-974 is a potent and specific inhibitor of PORCN. | |||||
| Targets | PORCN | |||||
| IC50 | ||||||
Quality Control & MSDS
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Chemical structure
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