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Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors
Open accessAbstract
Serine hydrolases (SHs) are a diverse enzyme class representing > 1% of all human proteins. The biological functions for most SHs remain poorly characterized due to a lack of selective inhibitors to probe their activity in living systems. Here, we show that a substantial number of SHs can be irreversibly inactivated by 1,2,3-triazole ureas, which exhibit 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 SH superfamily, including peptidases (acyl-peptide hydrolase or APEH), lipases (platelet-activating factor acetylhyrolase-2 or PAFAH2), and uncharacterized hydrolases (α, β-hydrolase 11 or ABHD11), with exceptional potency in cells (sub-nM) and mice (< 1 mg/kg). We show that APEH inhibition leads to accumulation of N-acetylated proteins and promotes proliferation in T-cells. These data designate 1,2,3-triazole ureas as a pharmacologically privileged chemotype for SH inhibition that shows broad activity across the SH class coupled with tunable selectivity for individual enzymes.
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Metadata
- Authors
- Adibekian, A., Martin, B. R., Wang, C., Hsu, K.-L., Bachovchin, D. A., Niessen, S., Hoover, H., & Cravatt, B. F.
- Venue
- Nature Chemical Biology
- Published
- 2011-05-15
- Volume
- 7
- Issue
- 7
- Pages
- 469-478
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2110112655
- Cited by
- 243
- References
- 5
- FWCI
- 11.97
- Type
- journal article
- Language
- en
- Open access
- green
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- Adibekian, A., Martin, B. R., Wang, C., Hsu, K.-L., Bachovchin, D. A., Niessen, S., Hoover, H., & Cravatt, B. F. (2011). Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors. Nature Chemical Biology. https://doi.org/10.1038/nchembio.579
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