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LGK974 is a highly potent, selective and orally bioavailable Porcupine inhibitor (Wnt signaling antagonist) with an IC₅₀ ~0.4 nM. LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV–Wnt1 and a human head and neck squamouscell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Currently LGK974 is in the Phase I study to treat cancers that are driven by the Wnt pathway in a Wnt ligand-dependent manner.

How to Use:

• In vitro:  LGK974 was suggested to be used at 0.1 µM final concentration in vitro to completely block Wnt protein secretion.
• In vivo:  LGK974 was used to dose mice orally at 0.1-10 mg/kg once or twice per day to achieve good efficacy in xenograft models.  

Reference:

• 1. Liu J, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. (2013) Proc Natl Acad Sci USA. 110(50):20224-9.
• 2. Jiang X, et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. (2013) Proc Natl Acad Sci USA. 110(31):12649-54. 
• 3. Shifeng Pan. Discovery of LGK974: A selective Porcupine inhibitor targeting Wnt signaling in cancer.  AACR Annual Meeting 2013.