Background
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]
参考文献:
[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
NCT-503 是一种磷酸甘油酸脱氢酶 (PHGDH) 抑制剂，IC50 为 2.5 μM[1]
用 NCT-503 处理三种 PHGDH 非依赖性细胞系和五种 PHGDH 依赖性细胞系表明，NCT-503 对 PHGDH 依赖性细胞系的 EC50 值为 8-16 μM，并且对其他 PHGDH 非依赖性细胞无毒性[1] 行。当测定 MHCC97L 细胞系中 NCT-503 的 GI50 时，发现 NCT-503 的处理显着降低了细胞中 NADPH/NADP+ 的相对比例。 NCT-503可使索拉非尼诱导的凋亡细胞数量增加一倍[2]
原代 MM 细胞对 PBMC 耐受的 PHGDH 抑制剂 NCT-503 剂量敏感[4]。在对厄洛替尼产生耐药性的肺腺癌 PC9ER4 细胞中，PHGDH 水平显着升高. NCT-503 对 PHGDH 的扰动增强了肿瘤杀伤作用并恢复了细胞系和异种移植物对厄洛替尼的敏感性。 NCT-503 [3]增强了 ROS 应激和 DNA 损伤标志物 γH2AX。NCT-503 和 Physcion 的联合治疗在体外和体内显着抑制肝细胞癌的生长[7]< /sup>
在小鼠中，NCT-503 表现出良好的吸收、分布、代谢和排泄 (ADME) 特性。 NCT-503 在腹膜内给药后具有良好的暴露、半衰期（2.5 小时）和 Cmax（血浆中 20 uM），并显着分配到肝脏和大脑中。 NCT-503 处理可降低 PHGDH 依赖性 MDA-MB-468 异种移植物的生长和重量，但不影响 PHGDH 非依赖性 MDA-MB-231 异种移植物的生长或重量[1]。在 C57BL 中/KaLwRij 小鼠被注射 5T33MM 细胞模型，NCT-503 治疗在所用剂量下并未降低肿瘤负荷，但与硼替佐米[4,5] 联合治疗时可降低肿瘤生长。将 NCT-503 添加到小鼠的饮食增加了体重和肝脏重量，并增加了肝脏中甘油三酯的含量。补充 NCT-503 可显着抑制 PHGDH 活性并降低肝脏中的丝氨酸含量[6]。用 NCT-503 处理小鼠和人肺成纤维细胞可降低 TGF-β 诱导的胶原蛋白合成。在气管内滴注博来霉素后 7 天开始使用 PHGDH 抑制剂 NCT-503 治疗的小鼠肺纤维化有所减轻[8]
Protocol
| Cell experiment [1]: |
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Cell lines
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MDA-MB-468 cells
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Preparation Method
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Cells were pretreated with 10 μM compound or an equivalent volume of DMSO in RPMI for 1 h.
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Reaction Conditions
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10 μM NCT-503,1h
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Applications
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NCT-503 treatment did not change intracellular glucose concentration
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| Animal experiment [2]: |
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Animal models
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Female NOD.CB17-Prkdcscid/J mice, 6–8 weeks old
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Preparation Method
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NCT-503 was prepared in a vehicle of 5% ethanol, 35% PEG 300, and 60% of an aqueous 30% hydroxypropyl-β-cyclodextrin (Sigma) solution, and injected intraperitoneally once daily.
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Dosage form
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30 mg/kg NCT-503 injected intraperitoneally once daily
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Applications
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NCT-503 treatment reduced the growth and weight of PHGDH-dependent MDA-MB-468 xenografts but did not affect those of PHGDH-independent MDA-MB-231 xenografts. PHGDH inhibition(NCT-503) also selectively increased necrosis in MDA-MB-468 but not MDA-MB-231 xenografts . Importantly, mice treated with the compound did not lose weight during the 24d treatment. Levels of NCT-503 in tumors were 3 μM at the conclusion of the experiment, validating exposure of the tumor to compound.
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参考文献:
[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.
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