Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction

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• 作者：Andrea Vaupel ; ^{andrea.vaupel@novartis.com" class="auth_mail} ; Guido Bold ; Alain De Pover ; Thé ; rè ; se Stachyra-Valat ; Joanna Hergovich-Lisztwan ; Joerg Kallen ; Keiichi Masuya ; Pascal Furet ; ^{pascal.furet@novartis.com" class="auth_mail}
• 关键词：Protein&ndash ; protein interaction inhibitors ; Structure-based design ; p53 ; MDM2
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 May, 2014
• 年：2014
• 卷：24
• 期：9
• 页码：2110-2114
• 全文大小：1590 K

文摘

Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line.