Second-Generation AUTACs for Targeted Autophagic Degradation
Daiki Takahashi, Taiichi Ora, Shigekazu Sasaki, Naoki Ishii, Toshio Tanaka, Takumi Matsuda, Mutsuki Ikeda, Jun Moriyama, Nobuo Cho, Hiroshi Nara, Hironobu Maezaki, Masahiro Kamaura, Kenichiro Shimokawa, Hirokazu Arimoto
Abstract
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.