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Biomacromolecule-mediated targeted protein degradation: an emerging strategy for cancer therapy

Meiyang Xi1, Fengxia Zhang2, Jingjing Zhu2

  • 1Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing, 312000, China; College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China.

European Journal of Medicinal Chemistry
|August 3, 2025
PubMed

Insights

Biomacromolecule conjugates, including degrader-antibody conjugates (DACs) and aptamer-PROTAC conjugates (APCs), offer novel strategies to overcome limitations of traditional cancer chemotherapeutics and proteolysis targeting chimeras (PROTACs). These advanced therapies aim for improved efficacy and reduced toxicity in cancer treatment.

Area of Science:

  • Biotechnology
  • Oncology
  • Drug Discovery

Background:

  • Conventional chemotherapy faces challenges like adverse effects and drug resistance.
  • Proteolysis targeting chimeras (PROTACs) show promise but have pharmacokinetic and toxicity issues.
  • Targeted delivery is crucial to enhance PROTAC efficacy and minimize off-tumor toxicity.

Purpose of the Study:

  • To review the mechanism and recent advances of biomacromolecule-PROTAC conjugates for cancer therapy.
  • To discuss the current challenges and future prospects of these targeted protein degradation strategies.

Main Methods:

  • Review of scientific literature on degrader-antibody conjugates (DACs) and aptamer-PROTAC conjugates (APCs).
  • Analysis of mechanisms, clinical progress, and preclinical developments.
  • Discussion of engineering strategies to improve PROTAC delivery and safety.

Main Results:

  • Several DACs are in clinical trials for cancer therapy.
  • Aptamer-PROTAC conjugates (APCs) demonstrate potential for better tissue penetration and lower immunogenicity in preclinical studies.
  • Bioconjugation strategies aim to overcome PROTAC limitations like poor permeability and toxicity.

Conclusions:

  • Biomacromolecule conjugates represent a promising frontier in targeted cancer therapy.
  • Further research and development are needed to address challenges and fully realize the potential of APCs and other conjugates.
  • These advanced modalities offer a path towards more effective and safer cancer treatments.
Keywords:
BiomacromoleculeCancer therapyProteolysis targeting chimera (PROTAC)

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