NCT-503 is a phosphoglycerate dehydrogenase (PHGDH) inhibitor with an IC₅₀ of 2.5 µM.

IC50: 2.5 µM (PHGDH)^[1]

Human phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step in the canonical glucose-derived serine synthesis pathway. NCT-503, a PHGDH inhibitor, inhibits serine synthesis from 3-phosphoglycerate in cells (IC₅₀=2.5 µM). NCT-503 is inactive against a panel of other dehydrogenases and shows minimal cross-reactivity in a panel of 168 GPCRs. Competition studies of NCT-503 against 3-phosphoglycerate (3-PG) and the co-substrate NAD⁺ reveal a non-competitive mode of inhibition with respect to both 3-PG and NAD⁺. NCT-503 has EC₅₀s of 8–16 µM for the PHGDH-dependent cell lines, a 6- to 10-fold higher EC₅₀ for MDA-MB-231 cells, and no toxicity towards other PHGDH-independent cell lines^[1].

NCT-503 exhibits favorable absorption, distribution, metabolism and excretion (ADME) properties. NCT-503 has good exposure, half-life (2.5 hr) and C_max (20 µM in plasma) following intraperitoneal administration with significant partitioning into the liver and brain. NCT-503 treatment reduces the growth and weight of PHGDH-dependent MDA-MB-468 xenografts but does not affect the growth or weight of PHGDH-independent MDA-MB-231 xenografts^[1].

• [1]. Pacold ME, et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol. 2016 Jun;12(6):452-8.