A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction
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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DOI：
10.1021/acschembio.6b00596
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发表时间：
2016-12-01
影响因子：
4
通讯作者：
Holak, Tad A.
中科院分区：
文献类型：
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作者：
Surmiak, Ewa;Twarda-Clapa, Aleksandra;Holak, Tad A.
在几乎所有类型的癌症中，p53 通路均因 p53 编码基因突变或 p53 负调节因子 Mdm2 和/或 Mdmx 过度表达而失活。通过抑制 p53-Mdm2/Mdmx 相互作用来恢复 p53 功能，为非基因毒性抗癌治疗开辟了前景。在这里，我们介绍了基于 3-吡咯啉-2-酮和 2-呋喃酮支架的两类新型 Mdm2-p53 抑制剂的合成、活性和晶体结构。这些抑制剂和 Mdm2 形成的复合物的结构揭示了迄今为止在小分子/Mdm2 复合物中尚未观察到的二聚体蛋白质分子组织。特别是，6-氯吲哚基团不占据 Mdm2 的常见 Trp-23 口袋，而是参与二聚化。化合物的这种完全独特的结合模式为优化 Mdm2 p53 相互作用抑制剂开辟了新的可能性。
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.