title: Combining cross-metathesis and activity-based protein profiling: new β-lactone motifs for targeting serine hydrolases.
abstract: β-Lactones are a privileged structural motif as enzyme inhibitors and chemical probes, particularly for the inhibition of enzymes from the serine hydrolase class. Herein, we demonstrate that cross-metathesis (CM) of α-methylene-β-lactones offers rapid access to structurally diverse, previously unexplored β-lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead β-lactone inhibitors/probes for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the α-methylene-β-lactone scaffold thus expands the landscape of serine hydrolases that can be targeted by small-molecule inhibitors and should further the functional characterization of enzymes from this class through the optimization of target-selective probes.
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs, CT 06269-3060, United States.
authors.forename: Kaddy
authors.initials: K
authors.lastname: Camara
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92307, United States.
authors.forename: Siddhesh S
authors.initials: SS
authors.lastname: Kamat
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs, CT 06269-3060, United States.
authors.forename: Celina C
authors.initials: CC
authors.lastname: Lasota
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92307, United States. Electronic address: cravatt@scripps.edu.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs, CT 06269-3060, United States. Electronic address: amy.howell@uconn.edu.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Howell
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002853:Chromatography, Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D020543:Proteome / Q000032:analysis*; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D007783:Lactones; D020543:Proteome; D015842:Serine Proteinase Inhibitors; C416683:methylene-lactone; D012697:Serine Endopeptidases
keywords: ABPP; Cross metathesis; Serine hydrolases; α-Methylene-β-lactones; β-Lactones