Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction
Journal article, 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 alpha-helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural alpha-helix. Conformational analysis indicated that 1,3,6-trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an alpha-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.

cancer-therapy

derivatives

p53 pathway

mutations

modulators

chemistry

rational design

oncoprotein

alpha-helix

protein-protein interactions

Author

Mariell Pettersson

University of Gothenburg

Maria Quant

University of Gothenburg

J. Min

St. Jude Children Research Hospital

L. Iconaru

St. Jude Children Research Hospital

R. W. Kriwacki

St. Jude Children Research Hospital

M. B. Waddell

St. Jude Children Research Hospital

R. K. Guy

St. Jude Children Research Hospital

Kristina Luthman

University of Gothenburg

Morten Grötli

University of Gothenburg

PLoS ONE

1932-6203 (ISSN) 19326203 (eISSN)

Vol. 10 10 e0137867

Subject Categories

Chemical Sciences

DOI

10.1371/journal.pone.0137867

More information

Latest update

5/21/2021