Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction

PLoS One. 2015 Oct 1;10(10):e0137867. doi: 10.1371/journal.pone.0137867. eCollection 2015.


The transcription factor p53 is the main tumour suppressor in cells and many cancer types have p53 mutations resulting in a loss of its function. In tumours that retain wild-type p53 function, p53 activity is down-regulated by MDM2 (human murine double minute 2) via a direct protein-protein interaction. We have designed and synthesised two series of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction. The first set was designed to directly mimic the α-helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural α-helix. Conformational analysis indicated that 1,3,6-trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an α-helix template. The key step of the synthesis involved the cyclisation of substituted dipeptides. The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis. This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Chemistry Techniques, Synthetic
  • Diketopiperazines / chemical synthesis*
  • Diketopiperazines / chemistry
  • Diketopiperazines / pharmacology*
  • Drug Design*
  • Humans
  • Models, Molecular
  • Protein Binding / drug effects
  • Protein Structure, Secondary
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*


  • Diketopiperazines
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2

Grants and funding

This study was supported by the Swedish Research Council (; project # 62120083533. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.