Dual functionality of MDM2 in PROTACs expands the horizons of targeted protein degradation.

Abstract

The evolution of targeted protein degradation (TPD) has been significantly propelled by the advent of proteolysis-targeting chimeras (PROTACs), which utilize heterobifunctional molecules to facilitate the ubiquitination-mediated degradation of previously "undruggable" proteins. Mouse double minute 2 (MDM2), which is often overexpressed in various diseases and plays a crucial role in regulating key pathways like p53, emerges as an exemplary candidate for therapeutic exploitation within the TPD realm, serving both as an intrinsic E3 ligase and as a direct protein of interest (POI). By harnessing MDM2's inherent E3 ligase activity, PROTACs have been designed to efficiently degrade specific POIs, achieving substantial success in both in vitro and in vivo studies. Alternatively, PROTACs have been developed to directly target MDM2 itself, offering new approaches for therapeutic intervention. Recent research has yielded valuable strategies for optimizing MDM2-harnessing and MDM2-targeted PROTAC designs, concentrating on warhead selection of POI, linker length and composition optimization, and the choice among various E3 ligases and their corresponding recruiters. These advancements not only broaden the scope of PROTAC technologies but also expedite the development of MDM2-based therapies, inspiring approaches for disease treatment.