Background: KRAS mutations are common in pancreatic ductal adenocarcinoma (PDAC). While 90% of PDAC tumors display activating mutations in KRAS, only ~2% are G12C, a specific KRAS mutation targeted by inhibitors such as sotorasib or adagrasib. MEK, which lies downstream of KRAS, is an attractive target to more broadly counteract elevated MAPK signaling regardless of the upstream mutation. However, FDA registered MEK inhibitors are prone to pathway reactivation events, which limit their utility in RAS mutant disease and necessitate chronic pathway inhibition that contributes to on-target toxicity. In contrast, IMM-1-104 is a novel, allosteric dual-MEK inhibitor designed to block pathway reactivation by disrupting phosphorylation of both MEK and ERK and has a short plasma drug half-life. These characteristics enable IMM-1-104 to drive deep cyclic MAPK pathway inhibition, with the potential to inhibit tumors driven by diverse RAS mutations.
