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Competitive Activity-Based Protein Profiling Identifies Aza-β-Lactams as a Versatile Chemotype for Serine Hydrolase Inhibition

Zuhl, Andrea M. and Mohr, Justin T. and Bachovchin, Daniel A. and Niessen, Sherry and Hsu, Ku-Lung and Berlin, Jacob M. and Dochnahl, Maximilian and López-Alberca, María P. and Fu, Gregory C. and Cravatt, Benjamin F. (2012) Competitive Activity-Based Protein Profiling Identifies Aza-β-Lactams as a Versatile Chemotype for Serine Hydrolase Inhibition. Journal of the American Chemical Society, 134 (11). pp. 5068-5071. ISSN 0002-7863. PMCID PMC3326416. doi:10.1021/ja300799t.

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Serine hydrolases are one of the largest and most diverse enzyme classes in Nature. Most serine hydrolases lack selective inhibitors, which are valuable probes for assigning functions to these enzymes. We recently discovered a set of aza-β-lactams (ABLs) that act as potent and selective inhibitors of the mammalian serine hydrolase protein-phosphatase methylesterase-1 (PME-1). The ABLs inactivate PME-1 by covalent acylation of the enzyme’s serine nucleophile, suggesting that they could offer a general scaffold for serine hydrolase inhibitor discovery. Here, we have tested this hypothesis by screening ABLs more broadly against cell and tissue proteomes by competitive activity-based protein profiling (ABPP), leading to the discovery of lead inhibitors for several serine hydrolases, including the uncharacterized enzyme α,β-hydrolase domain-containing 10 (ABHD10). ABPP-guided medicinal chemistry yielded a compound ABL303 that potently (IC₅₀ ≈ 30 nM) and selectively inactivated ABHD10 in vitro and in living cells. A comparison of optimized inhibitors for PME-1 and ABHD10 indicates that modest structural changes that alter steric bulk can tailor the ABL to selectively react with distinct, distantly related serine hydrolases. Our findings, taken together, designate the ABL as a versatile reactive group for creating first-in-class serine hydrolase inhibitors.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Mohr, Justin T.0000-0002-7005-3322
Berlin, Jacob M.0000-0001-7498-766X
Fu, Gregory C.0000-0002-0927-680X
Additional Information:© 2012 American Chemical Society, Received: January 24, 2012. Published: March 8, 2012. We thank B. Kipper, K. Masuda, D. Milliken, J. Murphy, H. Pugh, and K. Tsuboi for technical assistance. This work was supported by National Institutes of Health grants CA132630 and GM090294 (B.F.C.), GM57034 (G.C.F.), and GM086040 (postdoctoral fellowship to J.T.M.); the National Science Foundation (predoctoral fellowships to A.M.Z.. and D.A.B.); the California Breast Cancer Research Program (predoctoral fellowship to D.A.B.); Hewitt Foundation for Medical Research (postdoctoral fellowship to K.L.H.); the German Academic Exchange Service (postdoctoral fellowship to M.D.); Spanish Ministry of Education (FECYT, postdoctoral fellowship to M.P.L.A.); Abide Therapeutics; and The Skaggs Institute for Chemical Biology. The authors declare the following competing financial interest(s): Drs. Cravatt and Fu are advisors for a company interested in developing serine hydrolase inhibitors as new therapeutics.
Funding AgencyGrant Number
NIH Postdoctoral FellowshipGM086040
NSF Graduate Research FellowshipUNSPECIFIED
California Breast Cancer Research ProgramUNSPECIFIED
Hewitt Foundation for Medical ResearchUNSPECIFIED
Deutscher Akademischer Austauschdienst (DAAD)UNSPECIFIED
Fundación Española para la Ciencia y la Tecnología (FECYT)UNSPECIFIED
Abide TherapeuticsUNSPECIFIED
Skaggs Institute for Chemical BiologyUNSPECIFIED
Issue or Number:11
PubMed Central ID:PMC3326416
Record Number:CaltechAUTHORS:20200428-095145436
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Official Citation:Competitive Activity-Based Protein Profiling Identifies Aza-β-Lactams as a Versatile Chemotype for Serine Hydrolase Inhibition Andrea M. Zuhl, Justin T. Mohr, Daniel A. Bachovchin, Sherry Niessen, Ku-Lung Hsu, Jacob M. Berlin, Maximilian Dochnahl, María P. López-Alberca, Gregory C. Fu, and Benjamin F. Cravatt Journal of the American Chemical Society 2012 134 (11), 5068-5071 DOI: 10.1021/ja300799t
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102850
Deposited By: George Porter
Deposited On:29 Apr 2020 14:17
Last Modified:16 Nov 2021 18:16

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