Beyond PROTACs: Conditional Technologies and New Frontiers.

This chapter surveys the post-PROTAC landscape of targeted protein degradation (TPD), covering conditional activation, new degradation modalities, and proximity-driven editing of post-translational modifications (PTMs). Condition-activated PROTACs harness prodrugs responsive to irradiation or the tumor microenvironment and nanoparticle-based platforms to achieve spatiotemporally resolved protein degradation. The targetable space is further expanded by molecular glues that recruit neosubstrates to E3 ligases, endocytosis-lysosome targeting chimeras that clear extracellular and membrane proteins, and autophagy-lysosome strategies that degrade aggregates and damaged organelles. Ribonuclease-recruiting chimeras achieve targeted RNA degradation, while the induced-proximity concept is repurposed for PTM regulation, enabling targeted glycosylation, acetylation, and phosphorylation and dephosphorylation via the recruitment of glycosyltransferases, acetyltransferases, and kinases and phosphatases. Future advances in all-small-molecule-based conditional systems, brain-targeted delivery, and regulatory frameworks informed by degradation kinetics will embed stimulus sensing and logic-gated operations into intelligent molecular systems, shifting the paradigm toward on-demand proteome and transcriptome rewiring for precision medicine.