Research Progress on Small Molecule Inhibitors of MDM2-p53 Protein-protein Interaction.

The p53 protein, renowned as the "anti-cancer protein," plays a critical role in regulating the cell cycle, inducing apoptosis, and repairing DNA. Its dysregulation often leads to genomic instability and tumorigenesis. MDM2, a key negative feedback regulator of p53, inhibits both the transcriptional activity and stability of p53, thereby suppressing the anti-cancer effect of p53. With the resolution of the co-crystal structure of the MDM2- p53 complex, using small molecule inhibitors to block their interaction has emerged as a promising cancer treatment strategy. These inhibitors can remove the negative regulation of MDM2 on p53 and allow p53 to function as a "tumor suppressor protein". Over recent decades, researchers have designed and synthesized small-molecule inhibitors with diverse structures, showing notable anti-cancer efficacy in preclinical studies. Although several inhibitors have entered clinical trials, none have yet been approved. This review comprehensively summarizes the recent advancements in small-molecule inhibitors of MDM2-p53 protein-protein interaction (PPI) according to different types of structural scaffolds, primarily focusing on imidazolines, spirooxindoles, pyrrolidines, pyrrolones, piperidines, piperidines, purine carboxylic acid derivatives, isoquinolines, pyrazolopyrolidinone analogs, imidazothiazoles, quinolones, and spiroindolines. Additionally, this review focuses on their design, synthesis, and biological evaluation and highlights the structure-activity relationships and ongoing efforts. Despite the progress made, challenges remain. Researchers are exploring strategies to overcome these obstacles in promoting the research on drugs targeting MDM2-p53 PPI with stronger affinity, higher permeability, and a more significant effect.