Identification of a new p53/MDM2 inhibitor motif inspired by studies of chlorofusin

Marco Cominetti, Sarah Goffin, Ewan Raffel, Kerrie Turner, Jordann Ramoutar, Maria O'Connell, Lesley Howell, Mark Searcey

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Previous studies on the natural product chlorofusin have shown that the full peptide and azaphilone structure are required for inhibition of the interaction between MDM2 and p53. In the current work, we utilized the cyclic peptide as a template and introduced an azidonorvaline amino acid in place of the ornithine/azaphilone of the natural product and carried out click chemistry with the resulting peptide. From this small library the first ever non-azaphilone containing chlorofusin analogue with MDM2/p53 activity was identified. Further studies then suggested that the simple structure of the Fmoc-norvaline amino acid that had undergone a click reaction was also able to inhibit MDM2/p53 interaction. This is an example where studies of a natural product have led to the serendipitous identification of a new small molecule inhibitor of a protein-protein interaction.
Original languageEnglish
Pages (from-to)4878-4880
Number of pages3
JournalBioorganic & Medicinal Chemistry Letters
Issue number21
Early online date14 Jun 2015
Publication statusPublished - 1 Nov 2015


  • MDM2
  • Natural product
  • Protein-Protein Interactions
  • P53
  • Chlorofusin

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