University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
J Med Chem. 2021 Aug 12;64(15):10621-10640. doi: 10.1021/acs.jmedchem.1c00940. Epub 2021 Jul 21.
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.
MDM4 是 MDM2 的同源物，协同作为肿瘤抑制因子 p53 的负调节剂。在 MDM2 抑制剂的阴影下，对 MDM4 调节剂的发现投入的努力有限。最近对实验药物 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 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。已检查了配体/MDM4 复合物的晶体结构，并对其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。讨论了代表性的小分子 MDM4 抑制剂实例，随后介绍了 ALRN-6924 的临床结果，为进一步开发 MDM4 抑制剂（无论是双重抑制剂还是选择性抑制剂）提供了综合参考。
