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

Arlt, B.; Mastrobuoni, G.; Wuenschel, J.; Astrahantseff, K.; Eggert, A.; Kempa, S.; Deubzer, H.E.

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., Mastrobuoni, G., Wuenschel, J., Astrahantseff, K., Eggert, A., 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
ISSN:	1475-6366
Publisher:	Taylor & Francis
Volume:	36
Number:	1
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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