A Novel Lysosome Targeting Chimera for Targeted Protein Degradation via Split-and-Mix Strategy

• Published in: ACS chemical biology Vol. 19; no. 5; pp. 1161 - 1168
• Main Authors: Wang, Jinpeng, Wang, Yuechen, Yang, Fenfang, Luo, Qinhong, Hou, Zhanfeng, Xing, Yun, Lu, Fei, Li, Zigang, Yin, Feng
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17-05-2024
• Subjects: Autophagy - drug effects; Humans; Lysosomes - metabolism; Peptides - chemistry; Peptides - metabolism; Peptides - pharmacology; Proteolysis - drug effects
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.4c00092

Targeted protein degradation is becoming more and more important in the field of drug development. Compared with proteasomal-based degraders, lysosomal-based degraders have a broader target spectrum of targets, which have been demonstrated to have great potential, especially in degrading undruggable proteins. Recently, we developed a programmable and facile screening PROTAC development platform based on peptide self-assembly termed split-and-mix PROTAC (SM-PROTAC). In this study, we applied this technology for the development of lysosome-based degraders, named a split-and-mix chaperone-mediated autophagy-based degrader (SM-CMAD). We successfully demonstrated SM-CMAD as a universal platform by degrading several targets, including ERα, AR, MEK1/2, and BCR-ABL. Different from other lysosomal-based degraders, SM-CMAD was capable of facile screening with programmable ligand ratios. We believe that our work will promote the development of other multifunctional molecules and clinical translation for lysosomal-based degraders.