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PreprintCC BYChemRxiv

GCCDDCs Enable Tumor-Selective Lysosomal Degradation and Payload Delivery via GC-C-Mediated Trafficking

  • Yi Zhou1,2
  • Tengfei Liu
  • Huaihuai Shi
  • Xiaozhuo Tan
  • Hui Pan
  • Wenyan Dong
  • Wencong Pan
  • Jingjing Sun
  • Wu Su
  • Lijing Fang3,4
  • Guiyang Yao5,6
6 affiliations
  1. 1Guangxi Key Laboratory of Chemistry and Engineering of Forest Products
  2. 2Guangxi Minzu University
  3. 3Guangdong Key Laboratory of Nanomedicine
  4. 4Chinese Academy of Sciences
  5. 5School of Pharmacy
  6. 6Fudan University
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Abstract

Degrader–drug conjugates (DDCs) represent an emerging class of therapeutic agents that integrate the mechanism of targeted protein degradation with enhanced drug delivery, offering a promising strategy for precision cancer therapy. We herein report the rational design of GC-C–targeted degrader–drug conjugates (GCCDDCs), a bifunctional modality that promotes selective PD-L1 degradation while concurrently delivering a cytotoxic payload to GC-C–expressing cancer cells. Utilizing the GC-C agonist linaclotide as a targeting moiety, we first engineered GC-C–mediated lysosome-targeting chimeras (GCCTACs), which effectively induced degradation of both extracellular and membranebound proteins in a selective manner. By conjugating a PD-L1-targeting degrader to the microtubule-disrupting agent MMAE, the resulting GCCDDCs exhibit potent antitumor efficacy through coordinated immune checkpoint degradation and direct cytotoxicity. The development of GCCDDCs expands the pharmacological toolbox for targeted protein degraders (TPDs) and X–drug conjugates (XDCs), thereby offering broad utility in chemical

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Cite

BibTeXRIS
BibTeX
@misc{zhou2026gccddcs,
  title = {{GCCDDCs Enable Tumor-Selective Lysosomal Degradation and Payload Delivery via GC-C-Mediated Trafficking}},
  author = {Yi Zhou and Tengfei Liu and Huaihuai Shi and Xiaozhuo Tan and Hui Pan and Wenyan Dong and Wencong Pan and Jingjing Sun and Wu Su and Lijing Fang and Guiyang Yao},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15009517/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009517/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - GCCDDCs Enable Tumor-Selective Lysosomal Degradation and Payload Delivery via GC-C-Mediated Trafficking
AU  - Yi Zhou
AU  - Tengfei Liu
AU  - Huaihuai Shi
AU  - Xiaozhuo Tan
AU  - Hui Pan
AU  - Wenyan Dong
AU  - Wencong Pan
AU  - Jingjing Sun
AU  - Wu Su
AU  - Lijing Fang
AU  - Guiyang Yao
PY  - 2026
DA  - 2026/09/28
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009517/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009517/v1
AB  - Degrader–drug conjugates (DDCs) represent an emerging class of therapeutic agents that integrate the mechanism of targeted protein degradation with enhanced drug delivery, offering a promising strategy for precision cancer therapy. We herein report the rational design of GC-C–targeted degrader–drug conjugates (GCCDDCs), a bifunctional modality that promotes selective PD-L1 degradation while concurrently delivering a cytotoxic payload to GC-C–expressing cancer cells. Utilizing the GC-C agonist linaclotide as a targeting moiety, we first engineered GC-C–mediated lysosome-targeting chimeras (GCCTACs), which effectively induced degradation of both extracellular and membranebound proteins in a selective manner. By conjugating a PD-L1-targeting degrader to the microtubule-disrupting agent MMAE, the resulting GCCDDCs exhibit potent antitumor efficacy through coordinated immune checkpoint degradation and direct cytotoxicity. The development of GCCDDCs expands the pharmacological toolbox for targeted protein degraders (TPDs) and X–drug conjugates (XDCs), thereby offering broad utility in chemical
ER  -