Protein-protein interactions (PPIs) regulate a large number of pathways within cells and are now recognised as potential targets for therapeutic intervention. The p53/MDM2 interaction is a paradigm for PPI inhibition in cancer, with multiple compounds shown to inhibit the interaction and to have an antitumour effect, although no compounds have yet progressed to the clinic. Chlorofusin was the first natural product shown to inhibit the p53-MDM2 interaction. It is a cyclic nonapeptide conjugated to a bicyclic azaphilone through an ornithine side chain. Although the total synthesis of chlorofusin has been achieved and a small number of analogues have been explored, there is still little information with regard to the binding site or mechanism of action of the natural product. The purpose of this research was to produce novel analogues of chlorofusin to further explore the structure-activity relationships associated with MDM2 binding. Using our Fmoc-based solid phase approach to the production of the peptide, an azide was introduced in place of the ornithine amine enabling us to introduce defined, novel conjugation partners to the peptide through click chemistry. The results of the synthesis and biological studies of these compounds will be of interest in the design of new PPI inhibitors targeting p53/MDM2.

Targeting the p53-MDM2 interaction: Synthesis of novel chlorofusin analogs

248th National Meeting (2014)

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