Second-Generation AUTACs for Targeted Autophagic Degradation

Targeted protein degradation via the ubiquitin-proteasome
system
has emerged as one of the most promising drug discovery modalities.
Autophagy, another intracellular degradation system, can target a
wide range of nonproteinous substrates as well as proteins, but its
application to targeted degradation is still in its infancy. Our previous
work revealed a relationship between guanine modification of cysteine
residues on intracellular proteins and selective autophagy, resulting
in the first autophagy-based degraders, autophagy-targeted chimeras
(AUTACs). Based on the research background, all the reported AUTACs
compounds contain cysteine as a substructure. Here, we examine the
importance of this substructure by conducting SAR studies and report
significant improvements in the degrader’s activity by replacing
cysteine with other moieties. Several derivatives showed sub-μM
range degrading activity, demonstrating the increased practical value
of AUTACs.