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Development of Dual-Receptor Lysosome-Targeting Chimeras for Protein Degradation

Kun Wang1, Ke Wang2, Cong Wang2

  • 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Journal of the American Chemical Society
|October 23, 2025
PubMed

Insights

This study introduces a dual-targeting strategy using lysosome-targeting chimeras (LYTACs) to degrade disease-causing proteins like PD-L1 and EGFR. This novel approach enhances targeted protein degradation for potential cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Lysosome-targeting chimeras (LYTACs) are emerging therapeutics for targeted protein degradation.
  • Current LYTAC strategies face limitations in degrading specific extracellular and membrane proteins.

Purpose of the Study:

  • To develop a novel dual lysosome-targeting receptor-dependent protein degradation strategy.
  • To create dual-receptor LYTACs for efficient degradation of programmed cell death ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR).

Main Methods:

  • Leveraged synergistic actions of C-X-C chemokine receptor 4 (CXCR4) and folate receptor 1 (FOLR1).
  • Designed and tested dual-receptor LYTACs for PD-L1 and EGFR degradation.
  • Evaluated efficacy in preclinical models of EGFR-driven lung cancer.

Main Results:

  • Achieved efficient lysosomal degradation of PD-L1 and EGFR using dual-receptor LYTACs.
  • The EGFR-targeting chimera demonstrated significant inhibition of drug-resistant lung cancer tumor growth.
  • Dual-targeting strategy showed superior protein degradation compared to single-receptor LYTACs.

Conclusions:

  • The dual-targeting LYTAC strategy offers enhanced protein degradation capabilities.
  • This novel platform holds promise for developing advanced cancer therapeutics.
  • Dual-receptor targeting represents a significant advancement in protein degradation strategies for disease treatment.

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