MI-63

MI-63 is a potent, selective, non-peptide small-molecule inhibitor of the MDM2-p53 protein-protein interaction. Developed by the University of Michigan and licensed to Ascenta Therapeutics (later partnered with Sanofi), MI-63 binds to MDM2 with high affinity (Ki = 3 nM), mimicking key hydrophobic residues of p53 (Phe19, Trp23, and Leu26) to block the MDM2-p53 interaction. This inhibition prevents MDM2-mediated ubiquitination and degradation of p53, leading to the accumulation and activation of wild-type p53. Consequently, MI-63 induces p53-dependent cell cycle arrest (primarily in the G1 phase) and apoptosis in various cancer cell lines, including rhabdomyosarcoma, acute myeloid leukemia, multiple myeloma, and breast cancer. Due to its poor pharmacokinetic profile and susceptibility to isomerization in solution, MI-63 was not advanced to clinical trials but served as a critical lead compound for the design of more stable and orally bioavailable analogs, such as MI-219 and SAR405838.