How To Design a Successful p53-MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The protein-protein interaction between murine double minute (MDM) homologues MDM2/X and the tumor-suppressor protein p53 is a critical regulator of cancer development.
• Restoring the function of wild-type (WT) p53, known as the guardian of the genome, by inhibiting its negative regulators MDM2 and/or MDMX is a significant therapeutic strategy in oncology.

Purpose of the Study:

• To review small molecules and peptides that inhibit the p53-MDM2/X interaction.
• To categorize these inhibitors by scaffold type and discuss their properties.
• To highlight preclinical and clinical studies, with a focus on crystallographic structures and binding modes.

Main Methods:

• Review of published literature on small-molecule and peptide inhibitors of the p53-MDM2/X interaction.
• Categorization of inhibitors based on scaffold type.
• Analysis of available co-crystal structures and binding modes.

Main Results:

• Several classes of small molecules and peptides have been identified as potent, selective, and efficient inhibitors of the p53-MDM2/X interaction.
• Numerous co-crystal structures of these inhibitors with the protein targets are available, providing insights into binding modes.
• Preclinical and clinical data for these compounds are being actively investigated.

Conclusions:

• Inhibiting the p53-MDM2/X interaction is a validated therapeutic approach in oncology.
• Structural biology plays a crucial role in understanding and designing effective inhibitors.
• Ongoing research continues to advance the development of these targeted therapies.