PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective

Abstract

Mouse double minute 2 (MDM2) is an oncogenic E3 ligase that effectively degrades the tumor suppressor p53. In the past two decades, many MDM2 inhibitors that disrupt MDM2-p53 binding have been discovered and developed. Given that MDM2 and p53 form an auto-regulatory loop, in which p53 undergoes targeted degradation as a substrate of MDM2, and p53 targets MDM2 for transcriptional upregulation, these MDM2 inhibitors have limited efficacy. After rapidin vivoclearance of the MDM2 inhibitors, p53 is degraded by accumulated MDM2. Fortunately, proteolysis targeting chimeras (PROTACs), a novel therapeutic strategy, overcome the limitations of MDM2 inhibitors. Several MDM2 inhibitors developed in the past two decades have been used in PROTAC technology in two applications: 1) binding and targeting endogenous MDM2 for PROTAC-based degradation and 2) binding 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, and discuss future perspectives and challenges in their application as effective treatments for human cancer.