Patented small molecule inhibitors of p53-MDM2 interaction

The interaction between p53 and murine double minute 2 (MDM2) provides an attractive drug target in oncology. Small molecule inhibitors of this interaction have not only provided strong evidence for blocking the protein-protein interaction, but are also extremely useful as biological probes and ultimately as novel therapeutics. Here, a comprehensive review of the patented small molecule inhibitors of the p53-MDM2 interaction are provided. These inhibitors are divided into eight classes of compounds that include cis-imidazolines, benzodiazepines, fused indoles, substituted piperazines, substituted piperidines, aryl boronic acids, spiro-indoles, and alpha-helix mimetic compounds. The best documented class of compounds, cis-imidazolines (e.g., Nutlins) are selective and potent inhibitors of the p53-MDM2 interaction, and selected examples exhibit potency in the nanomolar range. Nutlins induce apoptosis in p53 wild-type cells and show in vivo efficacy in mice xenograft models. Additional strategies briefly discussed in this review, and which are under current exploration in targeting the p53 pathway, include the inhibition of MDM2-mediated p53 ubiquitylation and restoration of DNA-binding activity of mutant p53 protein using small molecules.