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

被引：18

作者：

Cominetti, Marco M. D. ^{[1
]}

Goffin, Sarah A. ^{[1
]}

Raffel, Ewan ^{[1
]}

Turner, Kerrie D. ^{[1
]}

Ramoutar, Jordann C. ^{[1
]}

O'Connell, Maria A. ^{[1
]}

Howell, Lesley A. ^{[1
]}

Searcey, Mark ^{[1
,2
]}

机构：

[1] Univ E Anglia, Sch Pharm, Norwich NR4 7TJ, Norfolk, England

[2] Univ E Anglia, Sch Chem, Norwich NR4 7TJ, Norfolk, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 21期

关键词：

p53; MDM2; Chlorofusin; Click chemistry; Protein-protein interactions; SOLID-PHASE SYNTHESIS; CYCLIC PEPTIDE; ASSIGNMENT;

D O I：

10.1016/j.bmcl.2015.06.014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 analog 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. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：4878 / 4880

页数：3

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