| 名稱 | Navoximod |
| 描述 | Navoximod (GDC-0919) (NLG- 919, GDC-0919) is a potent indoleamine-(2,3)-dioxygenase (IDO) pathway inhibitor (Ki/EC50: 7 nM/75 nM). |
| 細胞實驗 | Briefly, HeLa cells are seeded in a 96-well plate at a cell density of 5000 cells per well and allowed to grow overnight. Recombinant human IFN-γ is then added to each well with a final concentration of 50?ng/mL. At the same time, various concentrations of PEG2k-Fmoc-NLG(L), PEG2k-Fmoc-NLG(S) or Navoximod (NLG919) (50?nM-20?μM) are added to the cells. After 48?h of incubation, 150?μL of the supernatants per well is transferred to a new 96-well plate. Seventy-five μL of 30% trichloroacetic acid is added into each well and the mixture is incubated at 50°C for 30?min to hydrolyse N-formylkynurenine to kynurenine. For the colorimetric assay, supernatants are transferred to a new 96-well plate, mixed with an equal volume of Ehrlich reagent (2% p-dimethylamino-benzaldehyde w/v in glacial acetic acid), and incubated for 10?min at RT. The reaction product is measured at 490?nm by a plate reader [3]. |
| 動物實驗 | Mice are anesthetized with 4% isoflurane, and the surgical plane of anesthesia is maintained with 2% isoflurane in oxygen. Mice are immobilized in a stereotactic frame for tumor implantation. Briefly, the skull is shaved and exposed with a 0.5 cm skin incision. With the antiseptic technique, 10^5 GL261 cells (suspended in 3 μL RPMI-1640) are injected at the following coordinates with respect to the bregma on the right side (antero-posterior, -2 mm; medio-lateral, 2 mm; dorsoventral, 3 mm). This placement reproducibly yielded tumor growth in a paracortical area of the posterolateral right frontal lobe. Tumor-bearing mice are treated with combinations of oral DL-1MT (2 mg/mL D-1MT mixed with 2 mg/mL L-1MT) in drinking water, D-1MT (4 mg/mL) in drinking water, Navoximod (6 mg/mL) in drinking water, intraperitoneal cyclophosphamide, intraperitoneal temozolomide, and/or total-body radiation (500 cGy from a 137Cs source), as detailed in figure legends. Mice are observed daily and sacrificed when they became ill or moribund [2]. |
| 體外活性 | 在異基因混合淋巴細胞反應(MLR)中，使用表達IDO的人源單核細胞來源的樹突狀細胞(DCs)，Navoximod強力阻斷IDO引起的T細胞抑制并恢復強烈的T細胞反應(ED50：80 nM)。同樣，使用來自腫瘤引流淋巴結的表達IDO的小鼠DCs，Navoximod在體外消除IDO引起的特異性T細胞(OT-I)抑制(ED50：120 nM)[1]。Navoximod以濃度依賴的方式抑制IDO活性，其EC50為0.95μM。與游離的Navoximod相比，PEG2k-Fmoc-NLG(L)在抑制IDO方面活性較低(EC50：3.4μM)，而PEG2k-Fmoc-NLG(S)活性最低(EC50>10μM)。將表達IDO的腫瘤細胞與來自BALB/c小鼠的脾細胞共培養(yǎng)會顯著抑制T細胞的增殖。這種抑制在用Navoximod處理混合細胞時顯著減弱。PEG2k-Fmoc-NLG(L)也能逆轉腫瘤細胞的抑制效果，盡管其潛力略低于Navoximod[3]。 |
| 體內活性 | 在小鼠中，單次口服Navoximod可將血漿和組織中的Kyn濃度降低約50%。體內實驗顯示，在攜帶大型B16F10腫瘤的小鼠中，Navoximod的使用顯著增強了未激活的pmel-1細胞對含hgp100多肽及CpG-1826的IFA疫苗的抗腫瘤反應。在這個嚴格的已建立腫瘤模型中，Navoximod加上pmel-1/疫苗的組合在接種后的4天內顯著減少腫瘤體積（與僅接受pmel-1/疫苗而不使用Navoximod的對照動物相比，腫瘤體積減少約95%）[1]。當Navoximod與Temozolomide（TMZ）+放射治療（RT）結合使用時，相對于僅用TMZ+RT治療的小鼠，Navoximod和1-甲基-D-色氨酸（D-1MT，indoximod）均能提高生存率[2]。 |
| 存儲條件 | Store under nitrogen,
Pure form: -20°C for 3 years | In solvent: -80°C for 1 year
Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | 10% DMSO+90% Saline : < 10 mg/mL (31.61 mM), Lower concentrations may be soluble, but exact solubility limit is unknown.
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 10 mg/mL (31.61 mM), Solution.
DMSO : 150 mg/mL (474.13 mM), Sonication is recommended.
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| 關鍵字 | NLG-919 | NLG919 | NLG-?919 | NLG 919 | Navoximod | Inhibitor | inhibit | Indoleamine2,3Dioxygenase(IDO) | Indoleamine2,3Dioxygenase | Indoleamine 2,3-Dioxygenase (IDO) | Indoleamine 2,3Dioxygenase (IDO) | Indoleamine 2,3-Dioxygenase | IDO | GDC0919 | GDC 0919 |
| 相關產品 | IDO-IN-12 | Indoximod | Palmatine | TDO-IN-1 | GNF-PF-3777 | Necrostatin-1 | IDO-IN-7 | IDO1-IN-28 | Epacadostat | 3-TYP | Palmatine chloride | β-Lapachone |
| 相關庫 | 抑制劑庫 | 經典已知活性庫 | 抗癌活性化合物庫 | 已知活性化合物庫 | 抗癌細胞代謝庫 | 代謝化合物庫 | 臨床失敗化合物庫 | 含氟化合物庫 | 免疫/炎癥分子化合物庫 | 藥物功能重定位化合物庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |