Identification and characterization of novel human glucose-6-phosphate dehydrogenase inhibitors

J Biomol Screen. 2013 Mar;18(3):286-97. doi: 10.1177/1087057112462131. Epub 2012 Sep 27.


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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Aminonicotinamide / chemistry
  • 6-Aminonicotinamide / pharmacology
  • Cell Line, Tumor
  • Dehydroepiandrosterone / chemistry
  • Dehydroepiandrosterone / pharmacology
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Glucosephosphate Dehydrogenase / antagonists & inhibitors*
  • Glucosephosphate Dehydrogenase / chemistry*
  • Glucosephosphate Dehydrogenase / metabolism
  • High-Throughput Screening Assays / methods
  • Humans
  • Inhibitory Concentration 50
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology


  • Enzyme Inhibitors
  • Small Molecule Libraries
  • 6-Aminonicotinamide
  • Dehydroepiandrosterone
  • Glucosephosphate Dehydrogenase