New PROTAC Designs for Targeted Protein Degradation in 2021–2025: Novel E3 Ligases and Pre-PROTACs

Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative paradigm in pharmaceutical research. Despite significant progress in PROTACs, they are overwhelmingly dominated by the recruitment of a very restricted subset of canonical E3 ligases (e.g., CRBN and VHL), which hinders their potential therapeutic applications. As a result, recent developments have led to the emergence of PROTACs that utilize nonclassical E3 ligases. Another challenge is systemic toxicity caused by degradation on-target degradation in nonintended tissues, prompting the development of pre-PROTACs to achieve conditional and spatiotemporal modulation of target protein levels. Herein, we provide a comprehensive summary and discussion of recent advancements in PROTACs based on "novel" E3 ligases, as well as PROTAC prodrugs activated by external stimuli and the tumor microenvironment, highlighting prospects for the design of effective and selective PROTACs.