NCT-503

NCT-503 is a phosphoglycerate dehydrogenase (PHGDH) inhibitor with an IC50 of 2.5 µM^[1]

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]. When determined the GI50 of NCT-503 in the MHCC97L cell line and found that treatment of NCT-503 significantly reduced the relative ratio of NADPH/NADP+ in cells. NCT-503 could double the number of the apoptotic cells induced by Sorafenib^[2]

Primary MM cells are sensitive to doses of the PHGDH inhibitor NCT-503, that are tolerated by PBMCs^[4].PHGDH level was significantly increased in the lung adenocarcinoma PC9ER4 cells that acquired resistance to erlotinib. Perturbation of PHGDH by NCT-503, augmented the tumoricidal effect and restored sensitivity to erlotinib in cell lines and xenografts. ROS stress and DNA damage marker γH2AX were enhanced by NCT-503 ^[3].The combination treatment of NCT-503 and Physcion substantially inhibited hepatocellular carcinoma growth in vitro and in vivo^[7]

In mice, NCT-503 exhibits favorable absorption, distribution, metabolism and excretion (ADME) properties. NCT-503 has good exposure, half-life (2.5 hr) and Cmax (20 uM 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].In C57BL/KaLwRij mice were injected with 5T33MM cells model, NCT-503 treatment did not reduce tumor load at the doses used but reduced tumor growth in combination with bortezomib^[4,5].Adding NCT-503 to the diet of mice increased body weight and liver weight, and increased triglyceride content in liver. NCT-503 supplementation significantly inhibited PHGDH activity and decreased the serine content in the liver^[6].Treatment of murine and human lung fibroblasts with NCT-503 decreased TGF-β-induced collagen protein synthesis. Mice treated with the PHGDH inhibitor NCT-503 beginning 7 days after intratracheal instillation of bleomycin had attenuation of lung fibrosis^[8]

References:
[1]: Pacold ME, Brimacombe KR, et,al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol. 2016 Jun;12(6):452-8. doi: 10.1038/nchembio.2070. Epub 2016 Apr 25. Erratum in: Nat Chem Biol. 2016 Jul 19;12 (8):656. PMID: 27110680; PMCID: PMC4871733.
[2]: Wei L, Lee D, et,al. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat Commun. 2019 Oct 15;10(1):4681. doi: 10.1038/s41467-019-12606-7. PMID: 31615983; PMCID: PMC6794322.
[3]: Dong JK, Lei HM, et,al. Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase. Theranostics. 2018 Feb 12;8(7):1808-1823. doi: 10.7150/thno.23177. Erratum in: Theranostics. 2021 Feb 9;11(8):3963. PMID: 29556358; PMCID: PMC5858502.
[4]: Elsaadi S, Steiro I, et,al. Targeting phosphoglycerate dehydrogenase in multiple myeloma. Exp Hematol Oncol. 2021 Jan 4;10(1):3. doi: 10.1186/s40164-020-00196-w. PMID: 33397437; PMCID: PMC7784327.
[5]: Dong JK, Lei HM, et,al. Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase. Theranostics. 2018 Feb 12;8(7):1808-1823. doi: 10.7150/thno.23177. Erratum in: Theranostics. 2021 Feb 9;11(8):3963. PMID: 29556358; PMCID: PMC5858502.
[6]: He L, Liu Y, et,al. Exogenous and Endogenous Serine Deficiency Exacerbates Hepatic Lipid Accumulation. Oxid Med Cell Longev. 2021 Oct 19;2021:4232704. doi: 10.1155/2021/4232704. PMID: 34712382; PMCID: PMC8548146.
[7]: Dewdney B, Alanazy M, et,al. The effects of fructose and metabolic inhibition on hepatocellular carcinoma. Sci Rep. 2020 Oct 7;10(1):16769. doi: 10.1038/s41598-020-73653-5. PMID: 33028928; PMCID: PMC7541473.
[8]:Hamanaka RB, Nigdelioglu R, et,al. Inhibition of Phosphoglycerate Dehydrogenase Attenuates Bleomycin-induced Pulmonary Fibrosis. Am J Respir Cell Mol Biol. 2018 May;58(5):585-593. doi: 10.1165/rcmb.2017-0186OC. PMID: 29019702; PMCID: PMC5946329