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Self-assembled PROTACs enable glycoproteins degradation in the living cells

Haoyu Chen1, Liu Zang1, Pavel Kielkowski1

  • 1Department of Chemistry, LMU Munich Würmtalstr. 201 81375 Munich Germany pavel.kielkowski@cup.lmu.de.

Chemical Science
|April 10, 2025
PubMed

Insights

This study introduces GlyTAC, a novel proteolysis targeting chimera (PROTAC) strategy that degrades cancer cell glycoproteins. GlyTAC utilizes modified sugars to selectively eliminate target proteins, offering a potential new cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Aberrant protein glycosylation is a hallmark of cancer.
  • Targeting glycoproteins is a promising strategy for cancer therapy.
  • Proteolysis targeting chimeras (PROTACs) offer a method for targeted protein degradation.

Purpose of the Study:

  • To develop a novel PROTAC strategy targeting O-GalNAcylated and O-GlcNAcylated proteins.
  • To investigate the potential of this strategy for cancer therapy.
  • To leverage metabolic incorporation of modified sugars for targeted protein degradation.

Main Methods:

  • Metabolic incorporation of azido-modified N-acetylglucosamine (GlcNAc) or N-acetylgalactosamine (GalNAc) analogues into glycoproteins.
  • Strain-promoted azide-alkyne cycloaddition (SPAAC) to attach a thalidomide moiety, recruiting E3 ligase cereblon (CRBN).
  • Induction of ubiquitination and proteasomal degradation of targeted glycoproteins in human cancer cell lines.

Main Results:

  • Demonstrated selective degradation of O-GalNAcylated and O-GlcNAcylated proteins in cancer cells.
  • Observed significant toxicity in human cancer cell lines due to pathway perturbation.
  • Verified the mechanistic pathway through control experiments at each stage.

Conclusions:

  • GlyTAC is an efficient two-component PROTAC system for targeted glycoprotein degradation.
  • The strategy shows potential for cancer therapy due to cancer-specific glycosylation patterns.
  • Further investigation may lead to novel therapeutic approaches for cancer treatment.

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