The central valine concept provides an entry in a new class of non peptide inhibitors of the p53-MDM2 interaction

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• 作者：Pascal Furet ; ^{pascal.furet@novartis.com} ; Patrick Chè ; ne ; Alain De Pover ; Thé ; rè ; se Stachyra Valat ; Joanna Hergovich Lisztwan ; Joerg Kallen ; Keiichi Masuya
• 关键词：p53&ndash ; MDM2 inhibitors ; Protein&ndash ; protein interaction inhibitors ; Anticancer agents ; Structure-based design
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 May, 2012
• 卷：22
• 期：10
• 页码：3498-3502
• 文件大小：1059 K

摘要

Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein-protein interaction, we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53-MDM2 interaction.