KAHA ligation as a platform for the rapid discovery of Protein Tyrosine phosphatase 1B (PTP1B) inhibitors

Bioorg Chem. 2025 Jan:154:108028. doi: 10.1016/j.bioorg.2024.108028. Epub 2024 Dec 9.

Abstract

We have successfully designed and assembled a 66-member library of protein tyrosine phosphatases (PTP) inhibitor candidates using α-ketoacid-hydroxylamine (KAHA) ligation. Subsequent in situ enzymatic screening revealed a potent hit (IC50 = 1.67 μM) against PTP1B, which displayed 6.8- to 50-fold selectivity over other phosphatases.

Keywords: Chemoselective; Fragment-based library assembly; KAHA ligation; PTP1B inhibitors; Selective inhibitors.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Hydroxylamines / chemistry
  • Hydroxylamines / pharmacology
  • Molecular Structure
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship

Substances

  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Enzyme Inhibitors
  • PTPN1 protein, human
  • Hydroxylamines
  • Small Molecule Libraries