Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors

Blockade of aberrant Wnt signaling is an attractive therapeutic approachin multiple cancers. We developed and performed a cellular high-throughput screenfor inhibitors of Wnt secretion and pathway activation. A lead structure (GNF-1331) was identified from the screen. Further studies identified the molecular target of GNF-1331 as Porcupine, a membrane bound O-acyl transferase. Structure–activity relationshipstudies led to the discovery of a novel series of potent and selective Porcupineinhibitors. Compound 19, GNF-6231, demonstrated excellent pathway inhibition and induced robust antitumor efficacy in a mouse MMTV- WNT1xenograft tumor model.