IC50: 3.7 μM

NCT-502 is an inhibitor of 3-phosphoglycerate dehydrogenase (PHGDH).

Serine, a proteinogenic amino acid, is the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step in the canonical pathway of glucose-derived serine synthesis.

In vitro: NCT-502 was identified as an inhibitor of 3-phosphoglycerate dehydrogenase (PHGDH), inhibiting serine synthesis from 3-phosphoglycerate in cells. NCT-502 was inactive against a panel of other dehydrogenases and showed minimal cross-reactivity in a panel of 168 G-protein-coupled receptors. Moreover, In MDA-MB-231-PHGDH cells, NCT-502 treatment could decrease the intracellular serine and glycine concentrations and did not change the concentration of any other amino acid except for aspartate. In addition, NCT-502-mediated inhibition of serine synthesis was found to be reversible in cells [1].

In vivo: To evaluate the in-vivo activity NCT-503, a structurally close analog of NCT-502, NOD.SCID mice bearing MDA-MB-231 and MDA-MB-468 orthotopic xenografts were treated with vehicle or NCT-503. Results showed that NCT-503 reduced the growth and weight of PHGDH-dependent MDA-MB-468 xenografts but did not affect those of PHGDH-independent MDA-MB-231 xenografts. PHGDH inhibition caused by NCT-503 also selectively increased necrosis in MDA-MB-468 but not MDA-MB-231 xenografts. Importantly, mice treated with NCT-503 did not lose weight during the 24-d treatment [1].

Clinical trial: So far, no clinical study has been conducted.

Reference:
[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. Nature Chemical Biology 12(6), 452-458 (2016).