Autophagy-tethering compounds (ATTECs) as an emerging and potentially transformative drug discovery approach

Targeted protein degradation (TPD) strategies leveraging the ubiquitin-proteasome system (UPS), such as proteolysis-targeting chimeras (PROTACs), have gained wide recognition. While the UPS predominantly degrades short-lived soluble proteins, the lysosome-mediated system (LMS) excels at processing larger substrates, including protein aggregates, organelles, and macromolecular complexes. Recently, autophagy-tethering compounds (ATTECs) have emerged as a promising strategy for targeted degradation, harnessing the autophagy-lysosome system (ALS) to enable proximity-induced degradation. These heterobifunctional molecules, composed of LC3-binding warheads and TOI (target of interest) ligands linked together, provide therapeutic potential against disease-causing targets. This review outlines the therapeutic applications of ATTECs in human diseases, highlights recent progress in their development, and explores future opportunities for expanding this emerging class of degradation technologies through ALS from medicinal chemistry perspective.