Inhibiting PHGDH with NCT-503 reroutes glucose-derived carbons into the TCA cycle, independently of its on-target effect
| Autor: | Kathy Astrahantseff, Guido Mastrobuoni, Stefan Kempa, Hedwig E. Deubzer, Angelika Eggert, Jasmin Wuenschel, Birte Arlt |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Pyridines Citric Acid Cycle Cell RM1-950 cancer cell metabolism Gas Chromatography-Mass Spectrometry Piperazines Serine Drug control Cell Line Tumor Drug Discovery parasitic diseases medicine Humans Metabolomics Citrate synthase Phosphoglycerate dehydrogenase pulsed stable isotope-resolved metabolomics Enzyme Inhibitors de novo serine synthesis pathway Phosphoglycerate Dehydrogenase Cell Proliferation Pharmacology biology Chemistry Wild type General Medicine Pyruvate carboxylase Thioamides Citric acid cycle thermal shift assay Glucose medicine.anatomical_structure Biochemistry Cardiovascular and Metabolic Diseases biology.protein Therapeutics. Pharmacology CRISPR-Cas Systems Technology Platforms citrate synthase Research Article Research Paper |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 1282-1289 (2021) Journal of Enzyme Inhibition and Medicinal Chemistry article-version (VoR) Version of Record |
| Popis: | The small-molecule inhibitor of phosphoglycerate dehydrogenase, NCT-503, reduces incorporation of glucose-derived carbons into serine in vitro. Here we describe an off-target effect of NCT-503 in neuroblastoma cell lines expressing divergent phosphoglycerate dehydrogenase (PHGDH) levels and single-cell clones with CRISPR-Cas9-directed PHGDH knockout or their respective wildtype controls. NCT-503 treatment strongly reduced synthesis of glucose-derived citrate in all cell models investigated compared to the inactive drug control and independent of PHGDH expression level. Incorporation of glucose-derived carbons entering the TCA cycle via pyruvate carboxylase was enhanced by NCT-503 treatment. The activity of citrate synthase was not altered by NCT-503 treatment. We also detected no change in the thermal stabilisation of citrate synthase in cellular thermal shift assays from NCT-503-treated cells. Thus, the direct cause of the observed off-target effect remains enigmatic. Our findings highlight off-target potential within a metabolic assessment of carbon usage in cells treated with the small-molecule inhibitor, NCT-503. |
| Databáze: | OpenAIRE |
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