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

Cominetti, Marco, Goffin, Sarah, Raffel, Ewan, Turner, Kerrie, Ramoutar, Jordann, O'Connell, Maria ORCID:, Howell, Lesley and Searcey, Mark ORCID: (2015) Identification of a new p53/MDM2 inhibitor motif inspired by studies of chlorofusin. Bioorganic & Medicinal Chemistry Letters, 25 (21). pp. 4878-4880. ISSN 0960-894X

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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.

Item Type: Article
Uncontrolled Keywords: mdm2,natural product,protein-protein interactions,p53,chlorofusin
Faculty \ School: Faculty of Science > School of Pharmacy
Faculty of Science
Faculty of Science > School of Chemistry
Depositing User: Pure Connector
Date Deposited: 23 Oct 2015 09:00
Last Modified: 21 Oct 2022 00:57
DOI: 10.1016/j.bmcl.2015.06.014

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