title: Discovery of potent and selective inhibitors of human reticulocyte 15-lipoxygenase-1.
abstract: There are a variety of lipoxygenases in the human body (hLO), each having a distinct role in cellular biology. Human reticulocyte 15-lipoxygenase-1 (15-hLO-1), which catalyzes the dioxygenation of 1,4-cis,cis-pentadiene-containing polyunsaturated fatty acids, is implicated in a number of diseases including cancer, atherosclerosis, and neurodegenerative conditions. Despite the potential therapeutic relevance of this target, few inhibitors have been reported that are both potent and selective. To this end, we have employed a quantitative high-throughput (qHTS) screen against ∼74000 small molecules in search of reticulocyte 15-hLO-1 selective inhibitors. This screen led to the discovery of a novel chemotype for 15-hLO-1 inhibition, which displays nM potency and is >7500-fold selective against the related isozymes, 5-hLO, platelet 12-hLO, epithelial 15-hLO-2, ovine cyclooxygenase-1, and human cyclooxygenase-2. In addition, kinetic experiments were performed which indicate that this class of inhibitor is tight binding, reversible, and appears not to reduce the active-site ferric ion.
authors.affiliation: NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, MSC 3370, Bethesda, Maryland 20892, USA.
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.forename: Victor
authors.initials: V
authors.lastname: Kenyon
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: Lena
authors.initials: L
authors.lastname: Schultz
authors.forename: Michelle
authors.initials: M
authors.lastname: Armstrong
authors.forename: J Brian
authors.initials: JB
authors.lastname: Jameson
authors.forename: Eric
authors.initials: E
authors.lastname: Hoobler
authors.forename: William
authors.initials: W
authors.lastname: Leister
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D004952:Esters; D006801:Humans; D007700:Kinetics; D016859:Lipoxygenase Inhibitors; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D012156:Reticulocytes / Q000201:enzymology*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000480:Alkynes; D001565:Benzoates; D004952:Esters; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D010069:Oxadiazoles; D054852:Small Molecule Libraries; D013440:Sulfides; D013876:Thiophenes; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase