HTS4

HTS4 is a small molecule inhibitor of lysophosphatidylcholine acyltransferase 3 (LPCAT3) identified as a potential therapeutic for KRAS-mutant cancers. By inhibiting LPCAT3, HTS4 depletes polyunsaturated phosphatidylserine (PS) in the plasma membrane, which is essential for the nanoclustering and oncogenic signaling of mutant KRAS (e.g., G12D, G12V). This mechanism effectively mislocalizes KRAS from the plasma membrane and inhibits downstream MAPK signaling and tumor cell proliferation. Developed through collaboration between UTHealth Houston and The Scripps Research Institute, HTS4 represents a novel strategy to target diverse KRAS mutants by modulating the lipid environment required for their function, potentially addressing resistance issues seen with allele-specific KRAS inhibitors.