AUTOTAC

An autophagy targeting chimera (AUTOTAC) is a heterobifunctional small-molecule compound, comprising two active moieties connected by a linker, that specifically eliminates unwanted target proteins. This mode-of-action, in contrast to that of conventional enzyme inhibitors, harnesses selective intracellular proteolysis. AUTOTACs consist of two covalently-linked, protein-binding ligands: a target-binding ligand (TBL) that binds a protein-of-interest targeted for degradation, and an autophagy-targeting ligand (ATL) that engages the archetypal autophagic cargo receptor p62/SQSTM1 via its ZZ domain. TBLs can include but are not limited to bind to commercial drugs, on-going and/or failed candidates, and other general ligands. ATLs comprise p62-ZZ ligands that induce p62 self-oligomerization, global autophagic flux and autophagosome biogenesis . Thus, AUTOTACs provide a novel modality by sequestering and targeting pathological protein species to autophagic degradation. Kwon Yong-tae, a professor at Seoul National University, coined the term by establishing this concept.