title: Oxime esters as selective, covalent inhibitors of the serine hydrolase retinoblastoma-binding protein 9 (RBBP9).
abstract: We recently described a fluorescence polarization platform for competitive activity-based protein profiling (fluopol-ABPP) that enables high-throughput inhibitor screening for enzymes with poorly characterized biochemical activity. Here, we report the discovery of a class of oxime ester inhibitors for the unannotated serine hydrolase RBBP9 from a full-deck (200,000+ compound) fluopol-ABPP screen conducted in collaboration with the Molecular Libraries Screening Center Network (MLSCN). We show that these compounds covalently inhibit RBBP9 by modifying enzyme's active site serine nucleophile and, based on competitive ABPP in cell and tissue proteomes, are selective for RBBP9 relative to other mammalian serine hydrolases.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Bachovchin
authors.forename: Monique R
authors.initials: MR
authors.lastname: Wolfe
authors.forename: Kim
authors.initials: K
authors.lastname: Masuda
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Brown
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spicer
authors.forename: Virneliz
authors.initials: V
authors.lastname: Fernandez-Vega
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hodder
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology*; D020543:Proteome / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D004952:Esters; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D010091:Oximes; D020543:Proteome; C485185:RBBP9 protein, human