NCT-502

Novel inhibitor of homo sapiens phosphoglycerate dehydrogenase (PHGDH), reducing the production of glucose-derived serine in cells and suppressing the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors

What is NCT-502?

• NCT-502 is a small-molecule inhibitor of phosphoglycerate dehydrogenase (PHGDH).

• PHGDH is the first enzyme in the de novo serine biosynthesis pathway, converting 3-phosphoglycerate (a glycolytic intermediate) into 3-phosphohydroxypyruvate. This pathway supports cellular one-carbon metabolism, nucleotide synthesis, etc. 

Biochemical / Pharmacologic Properties

• NCT-502 has an IC₅₀ of ≈ 3.7 µM against PHGDH in enzymatic or cellular assays. 

• In differential scanning fluorimetry (DSF) assays, NCT-502 (and the related analog NCT-503) decreases the melting temperature (Tₘ) of PHGDH, consistent with binding and destabilization / conformational modulation. PMC

• It is reported to be reversible in its inhibition of serine production in cells. 

• The compound is selective: in early reports, NCT-502 was inactive against a panel of other dehydrogenases and had minimal cross-reactivity in a panel of ~168 G-protein–coupled receptors. 

Cellular / Biological Effects

• In PHGDH-dependent cancer cells, NCT-502 induces cytotoxicity or reduces viability, by impairing serine production from glucose.

• NCT-502 treatment leads to a drop in intracellular serine and glycine (which are downstream metabolites) in cell lines that depend on the de novo serine synthesis pathway. 

• It has been linked to promotion of ferroptosis (an iron-dependent nonapoptotic cell death mode) in certain cancer contexts, by weakening antioxidant defenses tied to one-carbon / redox metabolism. PMC

• In tumor models, inhibition of PHGDH (by analogs like NCT-503) reduced tumor growth selectively in PHGDH-high/PHGDH-dependent tumors. Although that is for NCT-503, it is often discussed together with NCT-502 in mechanistic studies. PMC

Mechanistic Considerations & Limitations

• Because NCT-502 targets PHGDH, its efficacy depends on whether the cell relies on de novo serine synthesis, as opposed to uptake of extracellular serine. Cells that can import serine may bypass the block.

• The potency (IC₅₀ ~ 3.7 µM) is moderate; for therapeutic or translational use, optimization (higher potency, better pharmacokinetics, in vivo stability) is likely needed.

• Off-target and toxicity profiles in vivo are less well characterized in literature (at least in the public domain).

• The reversible nature means that continuous exposure or dosing must be maintained for sustained inhibition.

• In heterogeneous tumor settings, only subsets of tumors (or regions thereof) may be sensitive depending on metabolic reprogramming.

0°C (short term), -20°C (long term), desiccated

NCT502; NCT 502

1) Pacold, M.E., Brimacombe, K.R., Chan, S.H., et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat. Chem. Biol. 12(6), 452-458 (2016).