Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction
Artikel i vetenskaplig tidskrift, 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.

modulators

alpha-helix

chemistry

mutations

p53 pathway

rational design

derivatives

cancer-therapy

oncoprotein

protein-protein interactions

Författare

Mariell Pettersson

Göteborgs universitet

Maria Quant

Chalmers, Kemi och kemiteknik, Tillämpad kemi, Polymerteknologi

J. Min

L. Iconaru

R. W. Kriwacki

M. B. Waddell

R. K. Guy

Kristina Luthman

Göteborgs universitet

Morten Grötli

Göteborgs universitet

PLoS ONE

1932-6203 (ISSN)

Vol. 10 10

Ämneskategorier

Kemi

DOI

10.1371/journal.pone.0137867

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Senast uppdaterat

2018-04-18