平方毫米
泛素连接酶
泛素
癌症研究
MDMX公司
下调和上调
抑制器
DNA连接酶
蛋白质降解
计算生物学
细胞生物学
生物
化学
癌症
生物化学
遗传学
酶
细胞凋亡
基因
作者
Xin Han,Wenyi Wei,Yi Sun
出处
期刊:Acta Materia Medica
[Compuscript, Ltd.]
日期:2022-01-01
卷期号:1 (2)
被引量:24
标识
DOI:10.15212/amm-2022-0010
摘要
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 in vivo 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.
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