title: 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.
authors.affiliation: Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9700 AD, Groningen, The Netherlands.
authors.forename: Natalia
authors.initials: N
authors.lastname: Estrada-Ortiz
authors.affiliation: Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9700 AD, Groningen, The Netherlands.
authors.forename: Constantinos G
authors.initials: CG
authors.lastname: Neochoritis
authors.affiliation: Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9700 AD, Groningen, The Netherlands. a.s.s.domling@rug.nl.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dömling
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D010455:Peptides; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; MDMX; cancer; conserved water; p53; protein-protein interactions