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

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

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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 Efeitos de diferentes frações inspiradas de oxigênio no índice biespectral em cães submetidos à infusão contínua de propofol Effects of several inspired oxygen fractions on the bispectral index in dogs submitted to continuous infusion of propofol of glucose-derived carbons entering the TCA cycle via pyruvate carboxylase was enhanced by NCT-503 treatment.The activity of citrate Bottom-up approach to strengthen community-based malaria control strategy from community health workers’ perceptions of their past, present, and future: a qualitative study in Palawan, Philippines 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.