title: Identification and characterization of novel human glucose-6-phosphate dehydrogenase inhibitors.
abstract: Glucose-6-phosphate dehydrogenase (G6PD) is the key enzyme of the pentose phosphate pathway, converting glucose-6-phosphate to 6-phosphoglucono-δ-lactone with parallel reduction of NADP(+). Several human diseases, including cancer, are associated with increased G6PD activity. To date, only a few G6PD inhibitors have been available. However, adverse side effects and high IC(50) values hamper their use as therapeutics and basic research probes. In this study, we developed a high-throughput screening assay to identify novel human G6PD (hG6PD) inhibitors. Screening the LOPAC (Sigma-Aldrich; 1280 compounds), Spectrum (Microsource Discovery System; 1969 compounds), and DIVERSet (ChemBridge; 49 971 compounds) small-molecule compound collections revealed 139 compounds that presented ≥50% hG6PD inhibition. Hit compounds were further included in a secondary and orthogonal assay in order to identify false-positives and to determine IC(50) values. The most potent hG6PD inhibitors presented IC(50) values of <4 µM. Compared with the known hG6PD inhibitors dehydroepiandrosterone and 6-aminonicotinamide, the inhibitors identified in this study were 100- to 1000-fold more potent and showed different mechanisms of enzyme inhibition. One of the newly identified hG6PD inhibitors reduced viability of the mammary carcinoma cell line MCF10-AT1 (IC(50) ~25 µM) more strongly than that of normal MCF10-A cells (IC(50) >50 µM).
authors.affiliation: University of California, San Diego, CA, USA.
authors.forename: Janina
authors.initials: J
authors.lastname: Preuss
authors.forename: Adam D
authors.initials: AD
authors.lastname: Richardson
authors.forename: Anthony
authors.initials: A
authors.lastname: Pinkerton
authors.forename: Michael
authors.initials: M
authors.lastname: Hedrick
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.forename: Stefan
authors.initials: S
authors.lastname: Rahlfs
authors.forename: Katja
authors.initials: K
authors.lastname: Becker
authors.forename: Lars
authors.initials: L
authors.lastname: Bode
mesh_terms: D015120:6-Aminonicotinamide / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003687:Dehydroepiandrosterone / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D015120:6-Aminonicotinamide; D003687:Dehydroepiandrosterone; D005954:Glucosephosphate Dehydrogenase