Toward effective Atg8‐based ATTECs: Approaches and perspectives

Abstract

Induction of Atg8‐family protein (LC3/GABARAP proteins in human) interactions with target proteins of interest by proximity‐inducing small molecules offers the possibility for novel targeted protein degradation approaches. However, despite intensive screening campaigns during the last 5 years, no potent ligands for LC3/GABARAPs have been developed, rendering this approach largely unexplored and unsuitable for therapeutic exploitation. In this Viewpoint, we analyze the reported attempts identifying LC3/GABARAP inhibitors and provide our own point of view why no potent inhibitors have been found. Additionally, we designate reasonable directions for the identification of potent and probably selective LC3/GABARAP inhibitors for alternative therapeutic applications.

Targeting LC3/GABARAP for degrader development and autophagy modulation

“…15 Similar to the E3 ligase dependent TPD, small molecules binding to LDS and the UDS probably interferes with cargo recruitment to LC3/GABARAP proteins and could be developed into small molecule degraders by recruitment of targets to the autophagosome. 16 However, discovery of potent LC3/GABARAP ligands has remained challenging, possibly due to the conformational plasticity of LC3/GABARAP resulting in at least partial occlusion of the LDS. 17 First, LC3A/B targeting reversible ligands such as the antibiotic Novobiocin 18 , covalent lysine targeting ligands 19 as well as a number of low molecular weight fragments (overviewed in Figure 1C) have been described binding to the LDS, 20 but no highly potent ligands or ligands for the four remaining LC3/GABARAPs have been described.…”