Second-Generation AUTACs for Targeted Autophagic Degradation

• Published in: Journal of medicinal chemistry Vol. 66; no. 17; pp. 12342 - 12372
• Main Authors: Takahashi, Daiki, Ora, Taiichi, Sasaki, Shigekazu, Ishii, Naoki, Tanaka, Toshio, Matsuda, Takumi, Ikeda, Mutsuki, Moriyama, Jun, Cho, Nobuo, Nara, Hiroshi, Maezaki, Hironobu, Kamaura, Masahiro, Shimokawa, Kenichiro, Arimoto, Hirokazu
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.09.2023; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; PROTEIN-DEGRADATION
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00861

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.