WNT-974

A potent and specific small-molecule Porcupine (PORCN) inhibitor with IC50 of 1 nM in the PORCN radioligand binding assay; potently inhibits Wnt signaling with IC50 of 0.4 nM, with no major cytotoxicity; reduces Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2; is potent and efficacious in multiple tumor models at well-tolerated doses in vivo.Colon Cancer Phase 2 Clinical (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. (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.