title: Selective inhibitor of platelet-activating factor acetylhydrolases 1b2 and 1b3 that impairs cancer cell survival.
abstract: Platelet-activating factor acetylhydrolases (PAFAHs) 1b2 and 1b3 are poorly characterized serine hydrolases that form a complex with a noncatalytic protein (1b1) to regulate brain development, spermatogenesis, and cancer pathogenesis. Determining physiological substrates and biochemical functions for the PAFAH1b complex would benefit from selective chemical probes that can perturb its activity in living systems. Here, we report a class of tetrahydropyridine reversible inhibitors of PAFAH1b2/3 discovered using a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) screen of the NIH 300,000+ compound library. The most potent of these agents, P11, exhibited IC50 values of ∼40 and 900 nM for PAFAH1b2 and 1b3, respectively. We confirm selective inhibition of PAFAH1b2/3 in cancer cells by P11 using an ABPP protocol adapted for in situ analysis of reversible inhibitors and show that this compound impairs tumor cell survival, supporting a role for PAFAH1b2/3 in cancer.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Zuhl
authors.forename: Anna E
authors.initials: AE
authors.lastname: Speers
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Brown
authors.affiliation: ⊥Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, California 94720, United States.
authors.forename: Melinda M
authors.initials: MM
authors.lastname: Mulvihill
authors.affiliation: #Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States.
authors.forename: Yi Chiao
authors.initials: YC
authors.lastname: Fan
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spicer
authors.forename: Mark
authors.initials: M
authors.lastname: Southern
authors.forename: Louis
authors.initials: L
authors.lastname: Scampavia
authors.forename: Virneliz
authors.initials: V
authors.lastname: Fernandez-Vega
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Dix
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hodder
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.affiliation: ⊥Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, California 94720, United States.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.affiliation: #Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States.
authors.forename: Ohyun
authors.initials: O
authors.lastname: Kwon
authors.forename: Ku-Lung
authors.initials: KL
authors.lastname: Hsu
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005454:Fluorescence Polarization / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D040901:Proteomics / Q000379:methods; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D011725:Pyridines; D054852:Small Molecule Libraries; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C000607175:PAFAH1b2 protein, mouse; C000607176:PAFAH1b3 protein, mouse