merodantoin

Merodantoin (also known as C1) is a novel small molecule therapeutic designed to target mutant KRAS-expressing cancers, specifically pancreatic ductal adenocarcinoma (PDAC). Unlike traditional KRAS inhibitors that aim to block the oncogene's activity, merodantoin utilizes a paradoxical approach by inducing KRAS activation-dependent, reactive oxygen species (ROS)-mediated ferroptosis. The compound triggers a cascade that increases intracellular and mitochondrial ROS, elevates labile iron levels through the upregulation of transferrin receptor 1 (TfR1) and downregulation of ferritin heavy chain (FTH1), and compromises the glutathione-based antioxidant system by inhibiting cystine uptake and reducing glutathione peroxidase 4 (GPX4) expression. This multi-pronged disruption leads to lethal lipid peroxidation. Merodantoin has demonstrated selective cytotoxicity against PDAC cells harboring G12 KRAS mutations and has shown efficacy in patient-derived organoids and orthotopic mouse models.