NCT-503

IC50: 2.5 μM for inhibiting serine synthesis from 3-phosphoglycerate in cells

NCT-503 is a 3-phosphoglycerate dehydrogenase (PHGDH) inhibitor.

In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) has been reported to catalyze the first, rate-limiting step.

In vitro: NCT-503 was identified as an inhibitor of PHGDH and was found to be inactive against a panel of other dehydrogenases and showed minimal cross-reactivity in a panel of G-protein-coupled receptors. In addition, treatment of three PHGDH-independent cell lines and five PHGDHdependent cell lines with NCT-503 demonstrated that NCT-503 had EC50 values of 8–16 μM for the PHGDH-dependent cell lines, and no toxicity toward other PHGDH-independent cell lines [1].

In vivo: To evaluate NCT-503 in-vivo activity, 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 treatment reduced the growth and weight of PHGDH-dependent xenografts but did not affect those of PHGDH-independent xenografts. Importantly, mice treated with NCT-503 did not lose weight during the 24-d treatment in spite of the potential systemic toxicities of inhibiting serine biosynthesis [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).