2. Academic Validation
  3. A Novel Lysosome Targeting Chimera for Targeted Protein Degradation via Split-and-Mix Strategy

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

  • ACS Chem Biol. 2024 Apr 25. doi: 10.1021/acschembio.4c00092.
Jinpeng Wang 1,  Yuechen Wang 1,  Fenfang Yang 2,  Qinhong Luo 1 3,  Zhanfeng Hou 1,  Yun Xing 1,  Fei Lu 1,  Zigang Li 1 4,  Feng Yin 1 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 2 Shenzhen Bay Laboratory, Shenzhen 518118, China.
  • 3 Department of Pharmacy, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China.
  • 4 Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen 518118, China.
PMID: 38662199 DOI: 10.1021/acschembio.4c00092
Abstract

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.

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