Proteomimetic libraries: design, synthesis, and evaluation of p53-MDM2 interaction inhibitors

J Comb Chem. 2006 May-Jun;8(3):315-25. doi: 10.1021/cc050142v.


The p53-MDM2 interaction regulates p53-mediated cellular responses to DNA damage, and MDM2 is overexpressed in 7% of all cancers. Structure-based computational design was applied to this system to design libraries centered on a scaffold that projects side chain functionalities with distance and angular relationships equivalent to those seen in the MDM2 interacting motif of p53. A library of 173 such compounds was synthesized using solution phase parallel chemistry. The in vitro competitive ability of the compounds to block p53 peptide binding to MDM2 was determined using a fluorescence polarization competition assay. The most active compound bound with K(d) = 12 microM, and its binding was characterized by (15)N-(1)H HSQC NMR.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Models, Molecular
  • Molecular Mimicry
  • Proto-Oncogene Proteins c-mdm2 / chemical synthesis*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / chemical synthesis*
  • Tumor Suppressor Protein p53 / metabolism


  • Enzyme Inhibitors
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2