Han Xin, Wei Wenyi, Sun Yi
Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
Cancer Center, Zhejiang University, Hangzhou 310014, China.
Acta Mater Med. 2022;1(2):244-259. doi: 10.15212/amm-2022-0010. Epub 2022 May 31.
Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase which effectively degrades tumor suppressor p53. In the past two decades, many MDM2 inhibitors that disrupt the MDM2-p53 binding have been discovered and developed. Given that the MDM2-p53 forms auto-regulatory loop in which p53 is a substrate of MDM2 for targeted degradation, while MDM2 is a p53 target for transcriptional upregulation, these MDM2 inhibitors have limited efficacy due to p53 degradation by accumulated MDM2 upon rapid clearance of the MDM2 inhibitors. Fortunately, proteolysis targeting chimeras (PROTACs), a novel therapeutic strategy, overcome the limitations of MDM2 inhibitors. Some of MDM2 inhibitors developed in the past two decades have been used in PROTAC technology for two applications: 1) as component 1 to bind with endogenous MDM2 as a target for PROTAC-based degradation of MDM2; and 2) as component 2 to bind with endogenous MDM2 as a PROTAC E3 ligand for PROTAC-based degradation of other oncogenic proteins. In this review, we summarize current progress in the discovery and development of MDM2-based PROTAC drugs with future perspectives and challenges for their applications in effective treatment of human cancer.
小鼠双微体2（MDM2）是一种E3泛素连接酶，可有效降解肿瘤抑制因子p53。在过去二十年中，已发现并开发了许多破坏MDM2-p53结合的MDM2抑制剂。鉴于MDM2-p53形成了一个自调节环，其中p53是MDM2靶向降解的底物，而MDM2是p53转录上调的靶点，这些MDM2抑制剂在快速清除MDM2抑制剂后，由于累积的MDM2导致p53降解，其疗效有限。幸运的是，靶向蛋白水解嵌合体（PROTACs）作为一种新型治疗策略，克服了MDM2抑制剂的局限性。在过去二十年中开发的一些MDM2抑制剂已用于PROTAC技术的两种应用：1）作为组分1与内源性MDM2结合，作为基于PROTAC的MDM2降解的靶点；2）作为组分2与内源性MDM2结合，作为基于PROTAC的其他致癌蛋白降解的PROTAC E3配体。在这篇综述中，我们总结了基于MDM2的PROTAC药物在发现和开发方面的当前进展，以及它们在有效治疗人类癌症中的应用所面临的未来前景和挑战。
