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

Blog Article

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 sten jacket m 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 g35 coupe fender potential within a metabolic assessment of carbon usage in cells treated with the small-molecule inhibitor, NCT-503.