Identification and Characterization of Novel Human Glucose-6-Phosphate Dehydrogenase Inhibitors

1University of California, San Diego, CA, USA.
Journal of Biomolecular Screening (Impact Factor: 2.42). 09/2012; 18(3). DOI: 10.1177/1087057112462131
Source: PubMed


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).

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Available from: Adam D Richardson, Apr 06, 2014
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    • "Doses of up to 200 mg/day have been given to large groups of subject for up to a year with very few side effects however supplementation results in at most a 25 fold increase in DHEA levels which is still lower than the 300 mM dose needed for G6PD inhibition [45]. There is active research looking for more potent, less androgenic DHEA analogs [46] [47] [48] and non-steroid G6PD inhibitors for cancer treatment [27]. Au is a gold phosphine that has been used safely in humans as an anti-rheumatoid arthritis drug for three decades and is an excellent inhibitor of both cytosolic and mitochondrial TrxR with an IC50 of 5–20 nM [33] [34]. "
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