title: A high throughput screen identifies potent and selective inhibitors to human epithelial 15-lipoxygenase-2.
abstract: Lipoxygenase (LOX) enzymes catalyze the hydroperoxidation of arachidonic acid and other polyunsaturated fatty acids to hydroxyeicosatetraenoic acids with varying positional specificity to yield important biological signaling molecules. Human epithelial 15-lipoxygenase-2 (15-LOX-2) is a highly specific LOX isozyme that is expressed in epithelial tissue and whose activity has been correlated with suppression of tumor growth in prostate and other epithelial derived cancers. Despite the potential utility of an inhibitor to probe the specific role of 15-LOX-2 in tumor progression, no such potent/specific 15-LOX-2 inhibitors have been reported to date. This study employs high throughput screening to identify two novel, specific 15-LOX-2 inhibitors. MLS000545091 is a mixed-type inhibitor of 15-LOX-2 with a Ki of 0.9+/-0.4 µM and has a 20-fold selectivity over 5-LOX, 12-LOX, 15-LOX-1, COX-1, and COX-2. MLS000536924 is a competitive inhibitor with a Ki of 2.5+/-0.5 µM and also possesses 20-fold selectivity toward 15-LOX-2 over the other oxygenases, listed above. Finally, neither compound possesses reductive activity towards the active-site ferrous ion.
authors.affiliation: Chemistry and Biochemistry Department, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: J Brian
authors.initials: JB
authors.lastname: Jameson
authors.affiliation: Chemistry and Biochemistry Department, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: Auric
authors.initials: A
authors.lastname: Kantz
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lena
authors.initials: L
authors.lastname: Schultz
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Kalyanaraman
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: Chemistry and Biochemistry Department, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
mesh_terms: D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004848:Epithelium / Q000201:enzymology; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011487:Protein Conformation
chemical_list: D016859:Lipoxygenase Inhibitors; D001093:Arachidonate 15-Lipoxygenase
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