MI-219

MI-219 is a potent, orally active small-molecule inhibitor of the MDM2-p53 protein-protein interaction. Developed by Ascenta Therapeutics and originally discovered at the University of Michigan, MI-219 specifically targets the p53-binding pocket of the MDM2 protein (the human homolog is often referred to as HDM2). By blocking this interaction, MI-219 prevents the MDM2-mediated ubiquitination and subsequent proteasomal degradation of the p53 tumor suppressor protein. This leads to the stabilization and reactivation of the p53 pathway, inducing cell cycle arrest and apoptosis in cancer cells that retain wild-type p53. Preclinical studies have demonstrated its efficacy in various solid tumor models, including pancreatic, colon, and breast cancers, often showing synergistic effects when combined with cytotoxic agents like oxaliplatin.