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

Mariell Pettersson ; Maria Quant (Institutionen för kemi och kemiteknik, Polymerteknologi) ; J. Min ; L. Iconaru ; R. W. Kriwacki ; M. B. Waddell ; R. K. Guy ; Kristina Luthman ; Morten Grøtli
PLoS ONE (1932-6203). Vol. 10 (2015), 10,
[Artikel, refereegranskad vetenskaplig]

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.

Nyckelord: protein-protein interactions, alpha-helix, rational design, cancer-therapy, p53 pathway, oncoprotein, derivatives, modulators, mutations, chemistry

Denna post skapades 2015-10-26. Senast ändrad 2015-11-02.
CPL Pubid: 224774


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Institutionen för kemi och molekylärbiologi (GU)
Institutionen för kemi och kemiteknik, Polymerteknologi



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