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Discovery of a Cell-Active SuTEx Ligand of Prostaglandin Reductase 2 |
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| Authors: | Emmanuel K. Toroitich Anthony M. Ciancone Heung Sik Hahm Skylar M. Brodowski Adam H. Libby Ku-Lung Hsu |
| Affiliation: | 1. Department of Chemistry, University of Virginia, Charlottesville, Virginia, 22904 USA These authors contributed equally to this work.;2. Department of Chemistry, University of Virginia, Charlottesville, Virginia, 22904 USA;3. Department of Chemistry, University of Virginia, Charlottesville, Virginia, 22904 USA University of Virginia Cancer Center, University of Virginia, Charlottesville, Virginia, 22903 USA |
| 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 chemical proteomics fragment-based ligand discovery SuFEx SuTEx |