Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein–Protein Interactions,Journal of Medicinal Chemistry

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Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein–Protein Interactions
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-07-21 , DOI: 10.1021/acs.jmedchem.1c00940
Shiyan Zhang _{1,

2} , Jianfeng Lou _{1,

2} , Yafang Li _{2,

3} , Feilong Zhou ₂ , Ziqin Yan ₂ , Xilin Lyu ₂ , Yujun Zhao _{1,

2,

4}

Affiliation

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.

中文翻译：

阻断 MDM4/p53 蛋白-蛋白相互作用的抑制剂的最新进展和临床开发

MDM4 是 MDM2 的同源物，协同作为肿瘤抑制因子 p53 的负调节因子。在 MDM2 抑制剂的阴影下，发现 MDM4 调节剂的努力有限。最近对实验药物 ALRN-6924（一种 MDM4 和 MDM2 双重抑制剂）的研究表明，同时抑制 MDM4 和 MDM2 可能比仅抑制 MDM2 更有益。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，包括基于肽的化合物和小分子。已经检查了配体/MDM4 复合物的共晶结构，并对它们的结构特征进行了编译和比较，以显示高 MDM4 结合亲和力所需的分子基础。讨论了小分子 MDM4 抑制剂的代表性例子，

更新日期：2021-08-12

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