Competitive Activity-Based Protein Profiling Identifies Aza-β-Lactams as a Versatile Chemotype for Serine Hydrolase Inhibition
Abstract
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.
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.Attached Files
Accepted Version - nihms362738.pdf
Supplemental Material - ja300799t_si_001.pdf
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Additional details
- PMCID
- PMC3326416
- Eprint ID
- 102850
- Resolver ID
- CaltechAUTHORS:20200428-095145436
- NIH
- CA132630
- NIH
- GM090294
- NIH
- GM57034
- NIH Postdoctoral Fellowship
- GM086040
- NSF Graduate Research Fellowship
- California Breast Cancer Research Program
- Hewitt Foundation for Medical Research
- Deutscher Akademischer Austauschdienst (DAAD)
- Fundación Española para la Ciencia y la Tecnología (FECYT)
- Abide Therapeutics
- Skaggs Institute for Chemical Biology
- Created
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2020-04-29Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field