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Inhibiting PHGDH with NCT-503 reroutes glucose-derived carbons into the TCA cycle, independently of its on-target effect

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Item Type:Article
Title:Inhibiting PHGDH with NCT-503 reroutes glucose-derived carbons into the TCA cycle, independently of its on-target effect
Creators Name:Arlt, B. and Mastrobuoni, G. and Wuenschel, J. and Astrahantseff, K. and Eggert, A. and Kempa, S. and Deubzer, H.E.
Abstract: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.
Keywords:Cancer Cell Metabolism, de novo Serine Synthesis Pathway, Citrate Synthase, Pulsed Stable Isotope-Resolved Metabolomics, Thermal Shift Assay
Source:Journal of Enzyme Inhibition and Medicinal Chemistry
Publisher:Taylor & Francis
Page Range:1282-1289
Date:30 June 2021
Official Publication:https://doi.org/10.1080/14756366.2021.1935917
PubMed:View item in PubMed

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