MI-43

MI-43 is a small-molecule, spiro-oxindole inhibitor designed to disrupt the protein-protein interaction between the E3 ubiquitin ligase MDM2 and the tumor suppressor protein p53. By binding with high affinity (Ki = 18 nmol/L) to the p53-binding pocket on the surface of MDM2, MI-43 prevents the ubiquitination and subsequent proteasomal degradation of p53. This inhibition leads to the stabilization and accumulation of wild-type p53, which subsequently activates downstream targets such as p21, resulting in cell cycle arrest and the induction of apoptosis in cancer cells. Although MI-43 demonstrated potent in vitro anti-tumor activity in colon and breast cancer models, its development was limited by a suboptimal pharmacokinetic profile, which precluded effective in vivo evaluation. This lead compound served as a structural basis for the development of more bioavailable analogues, such as MI-219.