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

Abstract

A recent therapeutic strategy in oncology is based on blocking the protein-protein interaction between the murine double minute (MDM) homologues MDM2/X and the tumor-suppressor protein p53. Inhibiting the binding between wild-type (WT) p53 and its negative regulators MDM2 and/or MDMX has become an important target in oncology to restore the antitumor activity of p53, the so-called guardian of our genome. Interestingly, based on the multiple disclosed compound classes and structural analysis of small-molecule-MDM2 adducts, the p53-MDM2 complex is perhaps the best studied and most targeted protein-protein interaction. Several classes of small molecules have been identified as potent, selective, and efficient inhibitors of the p53-MDM2/X interaction, and many co-crystal structures with the protein are available. Herein we review the properties as well as preclinical and clinical studies of these small molecules and peptides, categorized by scaffold type. A particular emphasis is made on crystallographic structures and the observed binding modes of these compounds, including conserved water molecules present.

Scaffold hopping via ANCHOR.QUERY: β-lactams as potent p53-MDM2 antagonists

“…Compounds 2a , 2c and 2d showed notable activity against MDMX as well, an interesting factor that most of the current inhibitors fail to combine. 5,26 Compounds 2f and 2g with different anchor did not show any activity.…”

“…25 The choice of the starting materials was based on our previous results on designing inhibitors of the p53-MDM2/X interaction. 26,27 Concerning the Phe19 pocket, we utilized bulky aliphatic isocyanides such as the tert-butyl ( 5a ) and the 1-adamantyl isocyanide ( 5b ) which were prepared by the classic dehydration of the corresponding formamide using POCl 3 .…”

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

“…To support the suggested interaction of synthesized compounds with MDM2, docking studies were applied, starting from the X-ray coordinates of the complex of the MI63-analogue with MDM2 [53–54]. The protein structure PDB ID 3LBL was chosen as the reference receptor because its ligand had high binding affinity and high resolution (1.6 Å).…”

Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows

“…MDM2 negatively regulates the p53 pathways and is often overexpressed in tumor cells. Different small molecule and stapled peptide-based drugs have been designed to inhibit the p53-MDM2 interaction [31, 32]. One of the very well-studied small molecule p53-MDM2 inhibitors is Nutlin-3 that exhibits anti-cancer effects even in those cells that do not express functional p53 via mechanisms involving p73 and E2F1 activation [33].…”