Manipulating autophagic degradation in human diseases: from mechanisms to interventions

Targeted degradation, having emerged as a powerful and promising strategy in drug discovery in the past two decades, has provided a solution for many once undruggable targets involved in various diseases. While earlier targeted degradation tools, as exemplified by PROteolysis-TArgeting Chimera (PROTAC), focused on harnessing the ubiquitin-proteasome system, novel approaches that aim to utilize autophagy, a potent, lysosome-dependent degradation pathway, have also surfaced recently as promising modalities. In this review, we first introduce the mechanisms that establish selectivity in autophagy, which provides the rationales for autophagy-based targeted degradation; we also provide an overview on the panoply of cellular machinery involved in this process, an arsenal that could be potentially harnessed. On this basis, we propose four strategies for designing autophagy-based targeted degraders, including Tagging Targets, Directly Engaging Targets, Initiating Autophagy at Targets, and Phagophore-Tethering to Targets. We introduce the current frontiers in this field, including AUtophagy-TArgeting Chimera (AUTAC), Targeted Protein Autophagy (TPA), AUTOphagy-TArgeting Chimera (AUTOTAC, not to be confused with AUTAC), AuTophagosome TEthering Compound (ATTEC), and other experimental approaches as case studies for each strategy. Finally, we put forward a workflow for generating autophagy-based degraders and some important questions that may guide and inspire the process.