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How To Design a Successful p53–MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures
Author(s) -
EstradaOrtiz Natalia,
Neochoritis Constantinos G.,
Dömling Alexander
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500487
Subject(s) - mdmx , mdm2 , small molecule , computational biology , suppressor , protein–protein interaction , chemistry , cancer research , biology , stereochemistry , biochemistry , gene
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.