生物活性

Navoximod (GDC-0919, NLG-919) 是一种有效的 IDO (indoleamine-(2,3)-dioxygenase) 途径的抑制剂，其Ki值为7 nM，EC50值为75 nM

体外研究

NLG919 potently blocks IDO-induced T-cell suppression and restored robust T-cell responses with ED50 of 80 nM. Similarly, using IDO-expressing mouse DCs from tumor-draining lymph nodes, NLG919 abrogated IDO-induced suppression of antigen-specific T cells (OT-I) in vitro, with ED50 of 120 nM. NLG919 increases the cytotoxic activity of paclitaxel toward B16-F10 cells in the presence of pretreatment with interferon (IFN)-γ in vitro

体内研究

In mice, a single oral administration of NLG919 reduces the concentration of plasma and tissue Kyn by ~ 50%. In mice bearing B16F10 tumors, NLG919 markedly enhances the antitumor responses of naive, resting pmel-1 cells to vaccination with cognate hgp100 peptide plus CpG-1826 in IFA. Immune competent mice are injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. GDC-0919 demonstrates potent inhibition of this node and effectively crosses the blood brain barrier. Although GDC-0919 as a single agent does not demonstrate anti-tumor activity, it has a strong potential for enhancing RT response in glioblastoma, which is further augmented with a hypofractionated regimen.

激酶实验

细胞实验

Cell lines: the murine melanoma cell line B16-F10 Concentrations: 100 nM Incubation Time: 12 h, 24 h, 48 h, 72 h Method: B16-F10 cells are diluted to 1 × 105 cells/mL with DMEM supplemented with 10% FBS and seeded at 2 mL per well into 6-well plates. The culture medium is replaced with fresh growth medium with or without 25 ng/mL IFN-γ for 10–12 h after seeding. After incubation with IFN-γ for 24 h, the medium is replaced with fresh medium containing 100 nM NLG919, 3 nM PTX, or a combination of 100 nM NLG919 and 3 nM PTX, and medium containing 0.1% DMSO is used as the vehicle treatment. PTX at 3 nM is a concentration with low inhibition rate (IR) of cell growth about 20%. At 0, 12, 24, 48, and 72 h after addition of drugs, cells are washed to remove dead cells and particles. Adherent cells are trypsinized and counted using a CountStar IC1000 Automated Cell Counter (Ruiyu-Biotech). Viability of the counted cells is confirmed by 0.1% trypan blue exclusion. The effect of NLG919 and PTX on the growth of cells

动物实验

Animal Models: C57BL/6 (H-2b, CD45.2) mice Dosages: 200 mg/kg Administration: Oral gavage

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

1.The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J Immunother Cancer. 2014 Jul 7;2:21.
2， An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy. Nat Commun. 2016 Nov 7;7:13443.
3.Tryptophan Metabolism Contributes to Radiation-Induced Immune Checkpoint Reactivation in Glioblastoma.Nature.2018 Aug 1;24(15):3632-3643
4，Combinatorial antitumor effects of indoleamine 2,3-dioxygenase inhibitor NLG919 and paclitaxel in a murine B16-F10 melanoma model.Nature.2017 Sep;30(3):215-226

体内溶解度

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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