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• W2110112655 abstract "Investigations of serine hydrolases have been frustrated by a lack of selective chemical inhibitors. Profiling of synthetically accessible 1,2,3-triazole ureas in cells and mice now identifies several effective compounds, application of which yields new insights into N-acetylation by APEH. 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." @default.
• W2110112655 created "2016-06-24" @default.
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• W2110112655 date "2011-05-15" @default.
• W2110112655 modified "2023-10-18" @default.
• W2110112655 title "Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors" @default.
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• W2110112655 doi "https://doi.org/10.1038/nchembio.579" @default.
• W2110112655 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3118922" @default.
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• W2110112655 hasPublicationYear "2011" @default.
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