Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein-Protein Interactions
Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein-Protein Interactions
复制标题
阻断 MDM4/p53 蛋白与蛋白相互作用的抑制剂的最新进展和临床开发
DOI：
10.1021/acs.jmedchem.1c00940
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发表时间：
2021-07-21
影响因子：
7.3
通讯作者：
Zhao, Yujun
中科院分区：
文献类型：
--
作者：
Zhang, Shiyan;Lou, Jianfeng;Zhao, Yujun
MDM4是MDM2的同源物，共同作为肿瘤抑制因子p53的负调控因子。在MDM2抑制剂的阴影下，对MDM4调节剂的发现力度有限。最近对实验性药物ALRN-6924（一种双重MDM4和MDM2抑制剂）的研究表明，同时抑制MDM4和MDM2可能比仅抑制MDM2有益。鉴于目前的研究进展，我们总结了已发表的MDM4/p53相互作用抑制剂，包括肽类化合物和小分子。研究了配体/ MDM4配合物的共晶结构，并对它们的结构特征进行了编译和比较，以揭示高MDM4结合亲和力所需的分子基础。本文讨论了具有代表性的小分子MDM4抑制剂，并结合ALRN-6924的临床结果，为进一步开发双重或选择性MDM4抑制剂提供了综合参考。
MDM4 is a homologue of MDM2, serving cooperatively as the negative regulator of tumor suppressor p53. Under the shadow of MDM2 inhibitors, limited efforts had been put into the discovery of MDM4 modulators. Recent studies of the experimental drug ALRN-6924, a dual MDM4 and MDM2 inhibitor, suggest that concurrent inhibition of MDM4 and MDM2 might be beneficial over only MDM2 inhibition. In view of the present research progress, we summarized published inhibitors of MDM4/p53 interactions including both peptide-based compounds and small molecules. Cocrystal structures of ligand/ MDM4 complexes have been examined, and their structural features were compiled and compared in order to show the molecular basis required for high MDM4 binding affinities. Representative examples of small-molecule MDM4 inhibitors were discussed, followed by clinical results of ALRN-6924, together, providing a consolidated reference for further development of MDM4 inhibitors, either dual or selective.