Journal
CHEMBIOCHEM
Volume 22, Issue 12, Pages 2134-2139Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202000879
Keywords
Activity-based protein profiling; chemical proteomics; fragment-based ligand discovery; SuFEx; SuTEx
Funding
- National Institutes of Health [DA043571]
- Robbins Family-MRA Young Investigator Award from the Melanoma Research Alliance
- University of Virginia Cancer Center (NCI Cancer Center Support Grant) [5P30CA044579-27]
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The study demonstrated the potential of SuTEx compounds in covalent modification of protein tyrosine sites and identified HHS-0701 as a cell-active inhibitor targeting prostaglandin reductase 2.
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.
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