A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction

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• 作者：Ewa Surmiak ; Aleksandra Twarda-Clapa ; Krzysztof M. Zak ; Bogdan Musielak ; Marcin D. Tomala ; Katarzyna Kubica ; Przemyslaw Grudnik ; Mariusz Madej ; Mateusz Jablonski ; Jan Potempa ; Justyna Kalinowska-Tluscik ; Alexander Dömling ; Grzegorz Dubin ; Tad A. Holak
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：December 16, 2016
• 年：2016
• 卷：11
• 期：12
• 页码：3310-3318
• 全文大小：579K
• ISSN：1554-8937

文摘

The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2–p53 interaction inhibitors.