Development of Dual-Receptor Lysosome-Targeting Chimeras for Protein Degradation
A growing array of lysosome-targeting chimeras (LYTACs) have recently emerged as therapeutic candidates to treat malignancies and other diseases via targeted protein degradation. We established a novel dual lysosome-targeting receptor-dependent protein degradation strategy that leverages the synergistic actions of the C-X-C chemokine receptor 4 (CXCR4) and folate receptor 1 (FOLR1) to degrade extracellular and membrane proteins. Using this strategy, we developed dual-receptor lysosome-targeting chimeras to achieve efficient lysosomal degradation of programmed cell death ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR). The EGFR chimera inhibited the growth of transplanted T790M-mutated drug-resistant EGFR-driven lung cancer tumors by degrading EGFR. This dual-targeting strategy exhibits significantly better protein degradation capabilities compared with single lysosome-targeting chimeras, providing a novel platform for developing drugs targeting cancer.
Authors
- Hailong Zhang (ORCID: https://orcid.org/0000-0002-0030-3234)
- Chen Gong (ORCID: https://orcid.org/0000-0002-9388-1171)
- Xuegong Fan (ORCID: https://orcid.org/0000-0001-8081-348X)
- Xudong Sun (ORCID: https://orcid.org/0000-0002-2434-8031)
- Guoxiong Zhou (ORCID: https://orcid.org/0000-0002-8432-9254)
- Kun Wang (ORCID: https://orcid.org/0000-0003-3282-4330)
- Rui Wang (ORCID: https://orcid.org/0000-0002-4719-9921)
- Ke Wang (ORCID: https://orcid.org/0000-0003-2117-9786)
- Hange Yang
- Juan Yi (ORCID: https://orcid.org/0009-0000-2180-0590)
- Peihong Ji
- Kuan Hu (ORCID: https://orcid.org/0009-0004-2549-629X)
- Cong Wang (ORCID: https://orcid.org/0009-0006-2448-3352)
Institutions
- Academy of Medical Sciences (GB)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking Union Medical College Hospital (CN)
- Gansu University of Traditional Chinese Medicine (CN)
- Shanghai Institute of Materia Medica (CN)
- Lanzhou University (CN)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1021/jacs.5c13695
- Citations
- 3
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.42