title: Click-generated triazole ureas as ultrapotent in vivo-active serine hydrolase inhibitors.
abstract: 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.
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Adibekian
authors.forename: Brent R
authors.initials: BR
authors.lastname: Martin
authors.forename: Chu
authors.initials: C
authors.lastname: Wang
authors.forename: Ku-Lung
authors.initials: KL
authors.lastname: Hsu
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Bachovchin
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Heather
authors.initials: H
authors.lastname: Hoover
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D045744:Cell Line, Tumor; D057930:Click Chemistry / Q000379:methods*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009206:Myocardium / Q000201:enzymology; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D014162:Transfection; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D015842:Serine Proteinase Inhibitors; D014230:Triazoles; D014508:Urea; D057057:Serine Proteases