title: Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A(2).
abstract: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2) or PLA(2)G7) binds to low-density lipoprotein (LDL) particles, where it is thought to hydrolyze oxidatively truncated phospholipids. Lp-PLA(2) has also been implicated as a pro-tumorigenic enzyme in human prostate cancer. Several inhibitors of Lp-PLA(2) have been described, including darapladib, which is currently in phase 3 clinical development for the treatment of atherosclerosis. The selectivity that darapladib and other Lp-PLA(2) inhibitors display across the larger serine hydrolase family has not, however, been reported. Here, we describe the use of both general and tailored activity-based probes for profiling Lp-PLA(2) and inhibitors of this enzyme in native biological systems. We show that both darapladib and a novel class of structurally distinct carbamate inhibitors inactivate Lp-PLA(2) in mouse tissues and human cell lines with high selectivity. Our findings thus identify both inhibitors and chemoproteomic probes that are suitable for investigating Lp-PLA(2) function in biological systems.
authors.affiliation: The Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, USA.
authors.forename: Joseph M G
authors.initials: JM
authors.lastname: Nagano
authors.forename: Ku-Lung
authors.initials: KL
authors.lastname: Hsu
authors.forename: Landon R
authors.initials: LR
authors.lastname: Whitby
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Niphakis
authors.forename: Anna E
authors.initials: AE
authors.lastname: Speers
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Brown
authors.forename: Timothy
authors.initials: T
authors.lastname: Spicer
authors.forename: Virneliz
authors.initials: V
authors.lastname: Fernandez-Vega
authors.forename: Jill
authors.initials: J
authors.lastname: Ferguson
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Prabhavathi
authors.initials: P
authors.lastname: Srinivasan
authors.forename: Tara D
authors.initials: TD
authors.lastname: Gonzalez
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bahnson
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors*; D000818:Animals; D001547:Benzaldehydes / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010091:Oximes / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D002219:Carbamates; D004791:Enzyme Inhibitors; D010091:Oximes; D010879:Piperazines; D011804:Quinolines; C581849:JMN4 compound; C581850:WWL153; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides