NCT-503 is a PHGDH inhibitor with IC50 value of 2.5μM, and exhibits less potency on PHGDH C234S. It reduced the production of glucose-derived serine in cells. Inhibition of PHGDH reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. NCT-503 showed selective and dose-dependent anti-proliferation on cells expressing PHGDH on high level, including HT1080, HCC70, BT-20, MDA-MB-468 and MT-3, at concentration ranging in 1-30μM. Consistent with this, administration of NCT-503 at dose of 40 mg/kg, i.p., daily reduced tumor growth of MDA-MB-468 orthotopic xenografts in vivo, accompanied with decreased production of glucose-derived serine but no changes in intratumoral serine concentrations.
作用机制
NCT-503 can bind to the PHGDH active site at cysteine 234.[1]
NCT-503 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Huh7 and A52
10, 25, or 50 µM
24 and 48 hours
NCT-503 significantly inhibited HCC tumor growth in vitro.
Sci Rep. 2020 Oct 7;10(1):16769.
Normal human lung fibroblasts (NHLFs)
30 µM
24 hours
Treatment with NCT-503 resulted in a dose-dependent decrease in the induction of collagen protein after TGF-β stimulation.
Am J Respir Cell Mol Biol. 2018 May;58(5):585-593.
NIH-3T3 cells
30 µM
24 hours
NCT-503 treatment reduced TGF-β-induced collagen protein accumulation.
Am J Respir Cell Mol Biol. 2018 May;58(5):585-593.
HCC
50 µM
48 hours
NCT-503 worked synergistically with Sorafenib to induce HCC cell apoptosis.
Nat Commun. 2019 Oct 15;10(1):4681.
BE(2)-C cells
10 µM
48 hours
To assess the impact of NCT-503 on cellular metabolism, results showed that NCT-503 significantly reduced synthesis of glucose-derived citrate and increased the conversion of glucose-derived carbons into malate.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):1282-1289.
SH-EP cells
10 µM
48 hours
To assess the impact of NCT-503 on cellular metabolism, results showed that NCT-503 significantly reduced synthesis of glucose-derived citrate and increased the conversion of glucose-derived carbons into malate.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):1282-1289.
Kelly cells
10 µM
96 hours
To assess the impact of NCT-503 on cell proliferation, results showed that NCT-503 significantly reduced cell viability.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):1282-1289.
SK-N-AS cells
10 µM
96 hours
To assess the impact of NCT-503 on cell proliferation, results showed that NCT-503 significantly reduced cell viability.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):1282-1289.
PC9ER4 cells
25 µM and 50 µM
NCT-503 significantly up-regulated the erlotinib sensitivity of PC9ER4 and HCC827ER9 cells.
Theranostics. 2018 Feb 12;8(7):1808-1823.
NCT-503 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Nude mice
Intraperitoneal injection
40 mg/kg
Daily administration
NCT-503 and Sorafenib combination therapy effectively abolished HCC growth.
Nat Commun. 2019 Oct 15;10(1):4681.
C57BL/6 and BALB/cFox1nu mice
HCC tumors
Intraperitoneal injection
40 mg/kg
Daily for 14 days
NCT-503 combined with Physcion significantly reduced HCC growth.
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