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Updated: Apr 21, 2026

A Converging Strategy for the Generation of a Virtually Sequenced cDNA Library from Unreferenced Pacific Oysters
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A Synergistic Inhibitor Development Strategy Against Human UDP-Galactose-4-Epimerase

William M Browne1,2, Jonathan Pettinger3, Teresa Weckwerth1,2

  • 1Chemical Glycobiology Laboratory, Francis Crick Institute, London, UK.

Angewandte Chemie (International Ed. in English)
|April 20, 2026
PubMed

Insights

Researchers developed novel small-molecule inhibitors for UDP-galactose-4-epimerase (GalE), a key enzyme in O-GalNAc glycosylation. This breakthrough offers new therapeutic strategies for cancer by targeting GalE, a promising oncology target.

Area of Science:

  • Biochemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • O-GalNAc glycosylation is a crucial posttranslational modification in mammals.
  • Its dysregulation is linked to cancer metastasis and immune evasion, but mechanistic insights are limited by a lack of chemical tools.
  • UDP-galactose-4-epimerase (GalE) is essential for O-GalNAc biosynthesis, making it a potential therapeutic target.

Purpose of the Study:

  • To develop novel small-molecule inhibitors targeting the enzyme GalE.
  • To establish an efficient workflow combining covalent and non-covalent fragment screening with structure-based design.
  • To identify potent inhibitors for GalE, addressing the need for chemical tools in O-GalNAc glycosylation research.

Main Methods:

  • Integrated covalent and high-throughput crystallographic non-covalent fragment screening.
  • Structure-based drug design strategies.
  • Identification of a ligandable pocket near a reactive tyrosine residue in GalE.

Main Results:

  • Discovery of a potent sulfonyl fluoride covalent inhibitor targeting a non-cysteine residue.
  • Development of a covalent alkyne probe.
  • Identification of nanomolar non-covalent and covalent binders using structure-enabled fragment screening.

Conclusions:

  • Demonstrated a synergistic approach for GalE inhibition using next-generation chemical matter.
  • Highlighted the potential for targeting non-cysteine residues in chemical biology.
  • Provided valuable tools for studying O-GalNAc glycosylation and developing new oncology therapeutics.
Keywords:
covalentdrug discoveryfragment‐basedglycosylationmetabolism

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