西亚试剂：Click-generated triazole ureas as ultrapotent in vivo–activ

Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors

Alexander Adibekian,1, 2 Brent R Martin,1, 2 Chu Wang,1, 2 Ku-Lung Hsu,1, 2 Daniel A Bachovchin,1, 2 Sherry Niessen,2, 3 Heather Hoover2, 3 & Benjamin F Cravatt1, 2

Serine hydrolases are a diverse enzyme class representing ～1% of all human proteins. The biological functions of most serine hydrolases remain poorly characterized owing to a lack of selective inhibitors to probe their activity in living systems. Here we show that a substantial number of serine hydrolases can be irreversibly inactivated by 1,2,3-triazole ureas, which show negligible cross-reactivity with other protein classes. Rapid lead optimization by click chemistry–enabled synthesis and competitive activity-based profiling identified 1,2,3-triazole ureas that selectively inhibit enzymes from diverse branches of the serine hydrolase class, including peptidases (acyl-peptide hydrolase, or APEH), lipases (platelet-activating factor acetylhydrolase-2, or PAFAH2) and uncharacterized hydrolases (α,β-hydrolase-11, or ABHD11), with exceptional potency in cells (sub-nanomolar) and mice (<1 mg kg?1). We show that APEH inhibition leads to accumulation of N-acetylated proteins and promotes proliferation in T cells. These data indicate 1,2,3-triazole ureas are a pharmacologically privileged chemotype for serine hydrolase inhibition, combining broad activity across the serine hydrolase class with tunable selectivity for individual enzymes.