Porcupine (PORCN) is a membrane bound O-acyltransferase that mediates palmitoylation of Wnt family proteins. This step is required for secretion and biologic activity of Wnt proteins, which have roles in embryonic development and cancer. Wnt-C59 is a potent inhibitor of PORCN, as measured by prevention of Wnt3A activation (IC50 = 74 pM). As palmitoylation of Wnt is required for its secretion, Wnt-C59 completely blocks Wnt3A secretion into culture media. Wnt-C59 prevents activation of all evaluated Wnt family members. This compound is effective in vivo as well as in vitro. Whether given by intravenous (2.5 mg/kg) or oral administration (5 mg/kg), Wnt-C59 displays a half-life in blood of approximately 1.94 hours, and remains greater than 10-fold above the in vitro IC50 concentration for at least 16 hours after a single oral dose. It blocks the progression of both basal-like and triple-negative breast cancers while downregulating Wnt/β-catenin pathway target genes in mice.
