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PROTAC Degraders with Ligands Recruiting MDM2 E3 Ubiquitin Ligase: An Updated Perspective
Xin Han1,2, Wenyi Wei3, Yi Sun1,2,4
1Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
Abstract:
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.
Insights
Proteolysis targeting chimeras (PROTACs) offer a novel therapeutic strategy to overcome limitations of traditional MDM2 inhibitors. MDM2-based PROTACs show promise for effective cancer treatment by degrading MDM2 or other oncogenic proteins.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that degrades the tumor suppressor p53.
- MDM2 inhibitors disrupt the MDM2-p53 binding but face limitations due to rapid in vivo clearance and p53 degradation by accumulated MDM2.
- The MDM2-p53 axis forms an auto-regulatory loop, complicating therapeutic interventions.
Purpose of the Study:
- To review the progress in discovery and development of MDM2-based proteolysis targeting chimeras (PROTACs).
- To explore the applications of MDM2-based PROTACs in cancer therapy.
- To discuss future perspectives and challenges for MDM2-based PROTACs.
Main Methods:
- Review of existing literature on MDM2 inhibitors and PROTAC technology.
- Analysis of the dual roles of MDM2 inhibitors in PROTAC design.
- Synthesis of current advancements in MDM2-based PROTAC drug development.
Main Results:
- PROTAC technology overcomes limitations of conventional MDM2 inhibitors.
- MDM2 inhibitors serve dual roles in PROTACs: as target binders or E3 ligand components.
- MDM2-based PROTACs are being developed for targeted degradation of MDM2 or other oncogenic proteins.
Conclusions:
- MDM2-based PROTACs represent a promising therapeutic strategy for human cancers.
- Further research and development are needed to address challenges and optimize applications.
- PROTACs offer a novel approach to target the MDM2-p53 pathway and other cancer-related targets.
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