title: 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 (IC(50) ≈ 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.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Zuhl
authors.forename: Justin T
authors.initials: JT
authors.lastname: Mohr
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Bachovchin
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Ku-Lung
authors.initials: KL
authors.lastname: Hsu
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Berlin
authors.forename: Maximilian
authors.initials: M
authors.lastname: Dochnahl
authors.forename: María P
authors.initials: MP
authors.lastname: López-Alberca
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Fu
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D015394:Molecular Structure; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D015842:Serine Proteinase Inhibitors; D047090:beta-Lactams; D012697:Serine Endopeptidases