title: Polypharmacology of Small-Molecule Modulators of the 5-Lipoxygenase Activating Protein (FLAP) Observed via a High-throughput Lipidomics Platform.
abstract: Leukotrienes (LTs) and related species are proinflammatory lipid mediators derived from arachidonic acid (AA) that have pathological roles in autoimmune and inflammatory conditions, cardiovascular diseases, and cancer. 5-Lipoxygenase activating protein (FLAP) plays a critical accessory role in the conversion of AA to LTA4, and its subsequent conversion to LTC4 by LTC4 synthase. Pharmacological inhibition of FLAP results in a loss of LT production by preventing the biosynthesis of both LTB4 and LTC4, making it an attractive target for the treatment of inflammatory diseases in which LTs likely play a role. Small-molecule (SM) drugs often exhibit polypharmacology through various pathways, which may explain the differential therapeutic efficacies of compounds sharing structural similarity. We have profiled a series of SM FLAP modulators for their selectivity across enzymes of AA cascade in human whole blood (HWB), using a recently developed LC/MS (liquid chromatography-mass spectrometry)-based high-throughput lipidomics platform that monitors 122 eicosanoids in multiplex. Highly efficient data acquisition coupled with fast and accurate data analysis allowed facile compound profiling from ex vivo study samples. This platform allowed us to quantitatively map the effects of those SMs on the entire AA cascade, demonstrating its potential to discriminate structurally related compounds.
authors.affiliation: Discovery Sciences, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Jiao
authors.initials: J
authors.lastname: Song
authors.affiliation: Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Mandana
authors.initials: M
authors.lastname: Tootoonchi
authors.affiliation: Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Keith
authors.affiliation: Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Meduna
authors.affiliation: Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Curt A
authors.initials: CA
authors.lastname: Dvorak
authors.affiliation: Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Eccles
authors.affiliation: Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Krawczuk
authors.affiliation: Discovery Sciences, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Blevitt
authors.affiliation: Discovery Sciences, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Jiejun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Navin L
authors.initials: NL
authors.lastname: Rao
authors.affiliation: Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
authors.forename: Alec D
authors.initials: AD
authors.lastname: Lebsack
authors.affiliation: Discovery Sciences, Janssen Research & Development, LLC, La Jolla, CA, USA mmilla22@its.jnj.com.
authors.forename: Marcos E
authors.initials: ME
authors.lastname: Milla
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000737:chemistry*; D015777:Eicosanoids / Q000737:chemistry; D005982:Glutathione Transferase / Q000737:chemistry; D006801:Humans; D015289:Leukotrienes / Q000737:chemistry; D064798:Polypharmacology; D054852:Small Molecule Libraries / Q000737:chemistry*
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D015777:Eicosanoids; D015289:Leukotrienes; D054852:Small Molecule Libraries; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase
keywords: FLAP inhibitors; compound differentiation; eicosanoids; lipidomics; polypharmacology