CGX1321

CGX1321 is an orally bioavailable, highly potent and selective small molecule inhibitor of the membrane-bound O-acyltransferase Porcupine (PORCN). By inhibiting PORCN, CGX1321 blocks the acylation and secretion of all WNT ligands, thereby suppressing both canonical and non-canonical WNT signaling pathways. This mechanism disrupts tumor growth driven by aberrant WNT signaling, particularly in tumors with RSPO fusions or inactivating RNF43 mutations. Preclinical studies have shown antitumor activity as well as potential benefits in conditions such as heart failure with preserved ejection fraction. The drug has been evaluated in phase 1 clinical trials for gastrointestinal cancers—including colorectal cancer—and other solid tumors, both as monotherapy and in combination with pembrolizumab.