HTS3

HTS3 is a small molecule inhibitor of lysophosphatidylcholine acyltransferase 3 (LPCAT3) that targets lipid metabolism to disrupt KRAS-driven oncogenesis. LPCAT3 is an enzyme that catalyzes the synthesis of unsaturated phosphatidylserine (PS), a lipid essential for the formation of KRAS signaling nanoclusters on the plasma membrane. By inhibiting LPCAT3, HTS3 depletes polyunsaturated PS levels, leading to the mislocalization of mutant KRAS (such as G12D and G12V) and the disruption of its signaling platforms. This results in reduced MAPK signaling, inhibited cell proliferation, and decreased colony formation in mutant KRAS-dependent pancreatic cancer cells. HTS3 represents a novel approach to targeting KRAS-dependent cancers by focusing on the lipid environment required for KRAS function, potentially addressing resistance issues associated with allele-specific inhibitors.