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Discovery and characterization of a novel glucose-6-phosphate dehydrogenase (G6PD) inhibitor via high-throughput screening.

Abstract
Altered glucose-6-phosphate dehydrogenase (G6PD) status is influential in many cellular pathophysiological processes and diseases, making G6PD a potential target for cancer therapy. However, the available G6PD inhibitors are very limited and restricted. Here we developed a reducing equivalent nicotinamide adenine dinucleotide phosphate (NADPH) absorption photometry assay based on enzyme kinetics to characterize G6PD activity. In this way, we performed a high-throughput screening (HTS) to an in house library. And then we identified compound named Wedelolactone inhibiting G6PD strongly in a non-competitive, reversible way. In addition, we did the surface Plasmon Resonance (SPR) assay and indicated the KD between Wedelolactone and G6PD protein was 3.64 μM. Furthermore, our basic colony formation assay showed the inhibitory effect of Wedelolactone on the proliferation of ovarian cancer cells (IC50 ~ 10 µM). Thus, we provided a high-throughput screening assay to quickly and efficiently discover G6PD inhibitors, and identified Wedelolactone as a G6PD inhibitor, implying that Wedelolactone suppresses ovarian cancer partly through targeting G6PD.
AuthorsZhongyuan Luo, Daohai Du, Yanjun Liu, Tian Lu, Liping Liu, Hualiang Jiang, Kaixian Chen, Changliang Shan, Cheng Luo
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 40 Pg. 127905 (05 15 2021) ISSN: 1464-3405 [Electronic] England
PMID33689874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 Elsevier Ltd. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Coumarins
  • Enzyme Inhibitors
  • wedelolactone
  • NADP
  • Glucosephosphate Dehydrogenase
Topics
  • Animals
  • Antineoplastic Agents (chemistry, pharmacology)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Coumarins (chemistry, pharmacology)
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors (chemistry, pharmacology)
  • Female
  • Glucosephosphate Dehydrogenase (antagonists & inhibitors)
  • High-Throughput Screening Assays
  • Humans
  • NADP (metabolism)
  • Ovarian Neoplasms (drug therapy)
  • Oxidation-Reduction
  • Protein Binding
  • Structure-Activity Relationship
  • Surface Plasmon Resonance

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