Design, synthesis and evaluation of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction

Mariell Pettersson, Maria Quant, Jaeki Min, Luigi Iconaru, Richard W. Kriwacki, M. Brett Waddell, R. Kiplin Guy, Kristina Luthman, Morten Grøtli

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish
Article numbere0137867
JournalPLoS ONE
Issue number10
StatePublished - Oct 1 2015

Bibliographical note

Publisher Copyright:
© 2015 Pettersson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ASJC Scopus subject areas

  • General


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