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

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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.
Funding Information
  • Beijing National Laboratory for Molecular Sciences (BNLMS20160112)
  • National Key Research and Development Program of China (2021YFC2103900)
  • Shenzhen Bay Laboratory
  • Science and Technology Foundation of Shenzhen City (JCYJ20200109140406047, JCYJ20220818095808019, RCJC20200714114433053)
  • National Natural Science Foundation of China (21977010)
  • Natural Science Foundation of Guangdong Province (2022A1515010996)
  • Shenzhen-Hong Kong Institute of Brain Science (2019SHIBS0004)
  • National Center for Biological Medicine Technology Innovation (NCTIB2022HS01017)
  • Tian Fu Jin Cheng Laboratory Group Racing Project (TFJC2023010008)
  • High-tech Zone Development Special Project of Shenzhen (29853M-KCJ-2023-002-07)

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