您好,欢迎来到试剂信息网! [登录] [免费注册]
试剂信息网
位置:首页 > 产品库 > Navoximod
立即咨询
咨询类型:
     
*姓名:
*电话:
*单位:
Email:
*留言内容:
请详细说明您的需求。
*验证码:
 
Navoximod
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
Navoximod图片
CAS NO:1402837-78-8
规格:≥98%
包装与价格:
包装价格(元)
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议
500mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW) 316.38
Formula C18H21FN2O2
CAS No. 1402837-78-8 (free base); 1793075-63-4 (phosphate salt)
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO:> 10mM
Water: N/A
Ethanol: N/A
Chemical Name (1R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol
Synonyms NLG-1488; IDO-IN-7; NLG 1488; IDOIN7; NLG1488; Navoximod; IDO IN 7
SMILES Code O[C@@H]([C@H]1CC[C@H](O)CC1)C[C@@H](C2=C3C=CC=C2F)N4C3=CN=C4
实验参考方法
In Vitro

In vitro activity: Navoximod (formerly known as IDO-IN-7 or NLG919) is a potent inhibitor of the IDO (indoleamine-(2,3)-dioxygenase) pathway with Ki/EC50 of 7 nM/75 nM. It has potential immunomodulating and antineoplastic activities. Navoximod was obtained by rational structural design based on the X-ray crystal structure for IDO complexed with 4-phenyl-imidazole (PIM). It is a strong competitive IDO inhibitor and potently inhibits IDO pathway in vitro and in cellular assays. In Phase Ia clinical trial for the treatment of advanced-stage solid tumors, Navoximod demonstrated the high dose tolerance (well tolerated up to 800 mg BID on a 21/28 day cycle), but revealed that single-agent therapy with an IDO inhibitor failed to cause tumor eradication and to prevent disease progression (best response was limited to stable disease in 7 out of 17 patients). Navoximod is now being evaluated in phase Ib in combination with PD-L1 inhibitor atezolizumab.


Kinase Assay: Navoximod inhibits the IDO activity in a concentration-dependent manner with an EC50 of 0.95 μM. PEG2k-Fmoc-NLG(L) is less active (EC50 of 3.4 μM) in inhibiting IDO compared with free Navoximod while PEG2k-Fmoc-NLG(S) is least active (EC50>10 μM). Coculture of IDO+tumor cells with splenocytes isolated from BALB/c mice leads to significant inhibition of T-cell proliferation. This inhibition is significantly attenuated when the mixed cells are treated with Navoximod. PEG2k-Fmoc-NLG(L) is also active in reversing the inhibitory effect of tumor cells although slightly less potent than Navoximod.


Cell Assay: Using IDO-expressing human monocyte-derived dendritic cells (DCs) in allogeneic mixed lymphocyte reaction (MLR) reactions, Navoximod (NLG919) potently blocks IDO-induced T cell suppression and restores robust T cell responses with an ED50=80 nM. Similarly, using IDO-expressing mouse DCs from tumor-draining lymph nodes, Navoximod abrogates IDO-induced suppression of antigen-specific T cells (OT-I) in vitro, with ED50=120 nM. The IDO inhibitory effect of PEG2k-Fmoc-NLG is tested by an in vitro IDO assay. 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 colorimetric assay, supernatants are transferred to a new 96-well plate, mixed with equal volume of Ehrlich reagent (2% p-dimethylamino-benzaldehyde w/v in glacial acetic acid), and incubated for 10 min at RT. Reaction product is measured at 490 nm by a plate reader

In VivoNavoximod (also known as NLG919) is orally bioavailable with F>70%, it has favorable pharmacokinetic and toxicity profiles. In mice, a single oral administration of Navoximod reduces the concentration of plasma and tissue Kyn by ~50%. In vivo, in mice bearing large established B16F10 tumors, administration of Navoximod markedly enhances the anti-tumor responses of naive, resting pmel-1 cells to vaccination with cognate hgp100 peptide plus CpG-1826 in IFA. In this stringent established-tumor model, Navoximod plus pmel-1/vaccine produce a dramatic collapse of tumor size within 4 days of vaccination (~95% reduction in tumor volume compare to control animals receiving pmel-1/vaccine alone without Navoximod)[1]. When combined with Temozolomide (TMZ)+radiation therapy (RT), both Navoximod and 1-methyl-D-tryptophan (D-1MT, indoximod) enhance survival relative to mice treated with TMZ+RT alone.
Animal model Mice
Formulation & Dosage Dissolved in water; 6 mg/mL
References Nat Commun. 2016 Nov 7;7:13443; J Immunother Cancer. 2014 Jul 7;2:21.