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Discovery of a Cell‐Active SuTEx Ligand of Prostaglandin Reductase 2
Author(s) -
Toroitich Emmanuel K.,
Ciancone Anthony M.,
Hahm Heung Sik,
Brodowski Skylar M.,
Libby Adam H.,
Hsu KuLung
Publication year - 2021
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202000879
Subject(s) - chemistry , ligand (biochemistry) , sulfonyl , biochemistry , protein tyrosine phosphatase , active site , tyrosine , electrophile , recombinant dna , enzyme , covalent bond , fusion protein , target protein , stereochemistry , receptor , alkyl , organic chemistry , gene , catalysis
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.