LGK974

LGK974 (WNT974) is an orally bioavailable and specific Porcupine (PORCN) inhibitor with an IC₅₀ of 0.1 nM^[1]. IC50 & Target: Porcupine^[1] In Vitro: LGK974 effectively displaces [³H]-GNF-1331 with an IC₅₀ of 1 nM in the PORCN radioligand binding assay. LGK974 potently reduces Wnt-dependent AXIN2 mRNA levels in HN30 cells with an IC₅₀ of 0.3 nM^[1]. In Vivo: LGK974, a drug that targets Porcupine, a Wnt-specific acyltransferase. LGK974 potently inhibits Wnt signaling, has strong efficacy in rodent tumor models, and is well-tolerated. Toxicology studies are performed on nontumor bearing rats at 3 and 20 mg/kg. At the efficacious dose of 3 mg/kg per day for 14 d, LGK974 is well-tolerated without abnormal histopathological findings in Wnt-dependent tissues, including the intestine, stomach, and skin. When rats are administrated a very high dose of 20 mg/kg per day for 14 d, loss of intestinal epithelium is observed, consistent with the concept that Wnt is required for intestinal tissue homeostasis^[1].