Small-molecule inhibitors of the p53-HDM2 interaction for the treatment of cancer

Abstract

Background: The hdm2 oncogene product, HDM2 (also known as MDM2), is an ubiquitin protein ligase that suppresses the transcriptional activity of the tumor suppressor p53 and promotes its degradation. Approximately 50% of all human tumors harbor mutations or deletions in the TP53 gene. In the remaining half of all human cancers that express the wild-type protein, aberrations of p53 regulators such as HDM2 account for p53 inhibition. Therefore, small-molecule inhibitors of the HDM2-p53 protein–protein interaction appear to offer an attractive strategy for cancer therapy. Objective: This review focuses on recent progress in the field of small-molecule inhibitors of the p53-HDM2 protein–protein interaction for the treatment of cancer. Results/conclusion: The development of pharmacological inhibitors has been challenging. Although many small-molecule HDM2 inhibitors have shown potent in vitro activity, only a limited number of compounds have displayed acceptable pharmacokinetic properties for in vivo evaluation. To date, the most studied chemotypes have been cis-imidazolines (e.g., Nutlins), benzodiazepines (BDPs) and spiro-oxindoles. The cis-imidazolines were the first reported potent, selective small-molecule inhibitors of the p53–MDM2 interaction, and continue to show therapeutic potential. Additionally, p53-based strategies involving inhibition of MDM2-mediated p53 ubiquitylation and restoration of DNA-binding activity of mutant p53 protein, as well as combination therapies, will be briefly described. Finally, a structurally distinct chemotype currently in Phase I clinical trials will be presented.