NCT-503

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

Signaling Pathways >> Others >> Others

Research Areas >> Cancer

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 Cmax (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].

MDA-MB-468, BT-20, MT-3 cells are seeded in white 96-well plates allowed to attach for 24 hours. Cells are treated with NCT-503 for four days. Cell viability is assessed with Cell Titer-Glo and luminescence measured with a plate reader[1].

Mice: Chronic catheters are surgically implanted into the jugular veins of normal or tumor bearing animals 3-4 days prior to infusions. Following administration of either vehicle or NCT-503 at 30 mg/kg, a constant infusion of U-13C-glucose (30 mg/kg/min) is administered for a 3-hour duration. Animals are terminally anesthetized with sodium pentobarbital and all tissues are fully harvested in less than 5 minutes to preserve the metabolic state. Tumors and adjacent lung tissue are carefully dissected and rapidly frozen for analysis[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.

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