Bifunctional proximity-inducing strategies for targeted and programmable post-translational modifications

The development of proteolysis-targeting chimeras (PROTACs) from their initial idea to their rise as a more comprehensive platform for proximity-driven regulation of protein function is traced in this review. We describe the design principles and mechanistic underpinnings of classical PROTAC architectures, and we talk about how these systems have evolved to include lysosomal, autophagic, and organelle-directed clearance pathways in addition to ubiquitin-proteasome-mediated degradation. Acknowledging the constraints imposed by existing degrader technologies-specifically, limited E3 ligase diversity and context-dependent efficacy- we highlight recent developments intended to address these issues. These include investigating novel E3 ligase repertoires, combining computational and AI-guided design approaches, and creating degradation platforms that can target biomolecules that were previously unreachable, like membrane proteins and RNA-associated complexes. The review also examines the development of biomolecular chimeras (BI-TACs), which extend targeted degradation across various cellular compartments, and next-generation proximity-based modalities, such as LYTACs, AUTACs, and RIBOTACs. Crucially, we address the concurrent emergence of functional modulation techniques mediated by engineered post-translational modifications and proximity-induced stabilization. Induced proximity can be used for protein rewiring and functional control in addition to degradation, as demonstrated by platforms like DUBTACs, PHICS, PHORCs, DEPTACs, ACETACs, RIPTACs, and TCIPs. Lastly, With the emergence of bacterial PROTACs (BacPROTACs), which show the versatility of proximity pharmacology across biological domains, we examine how targeted protein degradation has spread beyond mammalian systems. All of these developments point to a shift away from degradation-centric methods and toward a more comprehensive proximity pharmacology framework that can reshape protein fate, function, and therapeutic tractability.