Our group developed sulfonyl-triazoles as a new reactive group for covalent binding to catalytic and non-catalytic tyrosine sites on proteins through sulfur-triazole exchange chemistry (SuTEx). Here, we describe the application of SuTEx for fragment-based ligand discovery in live cells to develop a prostaglandin reductase 2 (PTGR2) ligand. PTGR2 reduces 15-keto-PGE<sub>2</sub> into 13,14-dihydro-15-keto-PGE<sub>2 </sub>lipid, which are critical for inflammatory and cancer signaling. We show by quantitative chemical proteomics that SuTEx fragment compounds ligand several tyrosine sites in the active site of PTGR2. Medicinal chemistry optimization produced first generation PTGR2 covalent inhibitors that show promising activity in live cells. While PTGR2 ligands are directed towards tyrosines located in the active site, we show in complementary studies that sulfonyl-triazoles are capable of binding regions remote from catalytic domains of lipid kinases by inclusion of appropriate recognition elements. We conclude with a discussion of how these cryptic lipid binding sites can be leveraged for development of selective inhibitors against related members of lipid enzyme superfamilies.

Developing targeted covalent inhibitors of lipid enyzmes through discovery of cryptic binding sites

ACS Spring 2022

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