biostudies-literatureToroitich EKHsu LaboratoryUVA Cancer CenterNIDA NIH HHSMelanoma Research AllianceNCI NIH HHSNational Institutes of HealthUniversity of Virginia Cancer CenterNCI Cancer Center Support2134-2139https://www.ebi.ac.uk/biostudies/studies/S-EPMC8206015biostudies-literatureUnknown22(12)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 Chembiochem : a European journal of chemical biologyDiscovery of a Cell-Active SuTEx Ligand of Prostaglandin Reductase 2.PMC82060155P30CA044579-27R01 DA043571DA043571P30 CA044579Hsu KLLibby AHBrodowski SMToroitich EKCiancone AMHahm HSfalseDiscovery of a Cell-Active SuTEx Ligand of 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 2021-01-01T00:00:00Z2021 Jun2025-04-22T03:14:25.963Z2025-02-18T23:32:16.766ZS-EPMC82060153386151910.1002/cbic.202000879