2. Academic Validation
  3. Discovery of a Cell-Active SuTEx Ligand of Prostaglandin Reductase 2

Discovery of a Cell-Active SuTEx Ligand of Prostaglandin Reductase 2

  • Chembiochem. 2021 Jun 15;22(12):2134-2139. doi: 10.1002/cbic.202000879.
Emmanuel K Toroitich 1,  Anthony M Ciancone 1,  Heung Sik Hahm 1,  Skylar M Brodowski 1,  Adam H Libby 1 2,  Ku-Lung Hsu 1 3 4 2
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Virginia, Charlottesville, Virginia, 22904, USA.
  • 2 University of Virginia Cancer Center, University of Virginia, Charlottesville, Virginia, 22903, USA.
  • 3 Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, 22908, USA.
  • 4 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, 22908, USA.
PMID: 33861519 DOI: 10.1002/cbic.202000879
Abstract

Sulfonyl-triazoles have emerged as a new reactive group for covalent modification of tyrosine sites on proteins through sulfur-triazole exchange (SuTEx) chemistry. The extent to which this sulfur electrophile can be tuned for developing ligands with cellular activity remains largely underexplored. Here, we performed fragment-based ligand discovery in live cells to identify SuTEx compounds capable of liganding tyrosine sites on diverse protein targets. We verified our quantitative chemical proteomic findings by demonstrating concentration-dependent activity of SuTEx ligands, but not inactive counterparts, against recombinant protein targets directly in live cells. Our structure-activity relationship studies identified the SuTEx ligand HHS-0701 as a cell-active inhibitor capable of blocking prostaglandin reductase 2 (PTGR2) biochemical activity.

Keywords

Activity-based protein profiling; SuFEx; SuTEx; chemical proteomics; fragment-based ligand discovery.

Figures
Products