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Purity: ≥98%
Navoximod (formerly known as IDO-IN-7; NLG-1488; NLG919) is a potent inhibitor of the IDO (indoleamine-(2,3)-dioxygenase) pathway (Ki/EC50 = 7 nM/75 nM) with 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.
| Targets |
Indoleamine 2,3-dioxygenase (IDO) (IC50 = 75 nM) [1]
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| ln Vitro |
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 an ED50=120 nM[1]. 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. With an EC50 of 0.95 μM, navoximod suppresses IDO activity in a concentration-dependent manner. When compared to free Navoximod, PEG2k-Fmoc-NLG(L) exhibits a lower EC50 of 3.4 μM for IDO inhibition, but PEG2k-Fmoc-NLG(S) exhibits the lowest EC50 of >10 μM. The coculture of IDO+tumor cells with BALB/c mouse splenocytes results in a notable suppression of T-cell proliferation. When Navoximod is administered to the mixed cells, this inhibition is greatly reduced. Though marginally less effective than Navoximod, PEG2k-Fmoc-NLG(L) is likewise active in reversing the inhibitory effect of tumor cells [3].
- Navoximod (NLG919; NLG-1488) inhibits IDO enzyme activity in vitro, reducing the conversion of tryptophan to kynurenine. In cell-based assays with IDO-expressing cells, treatment with Navoximod increases extracellular tryptophan levels and decreases kynurenine production, which is measured by high-performance liquid chromatography (HPLC) [1] - In murine glioblastoma cell lines, Navoximod (10 μM) enhances the anti-tumor effect of radiation in vitro by reversing IDO-mediated immunosuppression. It increases the proliferation of T cells co-cultured with glioblastoma cells, as detected by [³H]-thymidine incorporation assay [2] |
| ln Vivo |
Orally bioavailable (F>70%), vNavoximod (NLG919) has a good pharmacokinetic and toxicological profile. A single oral dose of navoximod in mice lowers tissue Kyn and plasma concentrations by approximately 50%. Navoximod treatment significantly increases the anti-tumor responses of naïve, resting pmel-1 cells following immunization with homologous hgp100 peptide plus CpG-1826 in IFA in vivo in mice carrying large developed B16F10 tumors. When compared to control mice who received pmel-1/vaccine alone without Navoximod, Navoximod plus pmel-1/vaccine resulted in a significant collapse of tumor growth within 4 days of immunization (~95% reduction in tumor volume)[1]. Compared to mice treated with NSC 362856 (TMZ)+RT alone, both Navoximod and D-1MT (Indoximod) improve survival when paired with these treatments[2].
- In a murine glioblastoma model (GL261 cells implanted intracranially), combination treatment with Navoximod, chemotherapy (temozolomide), and radiation significantly improves survival compared to single or dual treatments. The combination reduces tumor growth, increases CD8⁺ T cell infiltration into tumors, and decreases regulatory T cell (Treg) numbers, as analyzed by flow cytometry [2] - In a murine breast cancer model (4T1 cells implanted subcutaneously), Navoximod loaded in a dual-functional nanocarrier (with paclitaxel) inhibits tumor growth more effectively than single-agent treatment or free drugs. The combination increases intratumoral CD8⁺ T cell infiltration and reduces Tregs, while promoting M1 macrophage polarization, as shown by immunohistochemistry and flow cytometry [3] |
| Enzyme Assay |
Recombinant IDO enzyme is incubated with Navoximod at various concentrations (0.01-1000 nM) in a reaction buffer containing tryptophan and cofactors. The enzyme activity is measured by quantifying the production of kynurenine using HPLC. The IC50 value is determined from the dose-response curve of IDO inhibition [1]
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| Cell Assay |
- For IDO activity assessment: IDO-expressing cells are treated with Navoximod (0.1-10 μM) for 24-48 hours. Supernatants are collected, and tryptophan/kynurenine levels are measured by HPLC to evaluate IDO inhibition [1]
- For T cell proliferation assay: Murine glioblastoma cells are pretreated with Navoximod (10 μM) and irradiated, then co-cultured with splenic T cells. T cell proliferation is measured by [³H]-thymidine incorporation after 72 hours [2] - Animal Protocol: - For murine glioblastoma model: Mice with intracranial GL261 tumors are treated with Navoximod (100 mg/kg) via oral gavage once daily, combined with temozolomide (50 mg/kg, intraperitoneal injection, daily for 5 days) and radiation (10 Gy, single dose on day 7). Survival is monitored, and tumors are analyzed for immune cell infiltration [2] - For breast cancer nanocarrier study: Mice with subcutaneous 4T1 tumors receive intravenous injections of the nanocarrier loaded with Navoximod (dose equivalent to 5 mg/kg) and paclitaxel (5 mg/kg) once every 3 days for 4 cycles. Tumor volume is measured every 2 days, and tissues are collected for immune cell profiling [3] |
| Animal Protocol |
Dissolved in water; 6 mg/mL
Mice - For murine glioblastoma model: Mice with intracranial GL261 tumors are treated with Navoximod (100 mg/kg) via oral gavage once daily, combined with temozolomide (50 mg/kg, intraperitoneal injection, daily for 5 days) and radiation (10 Gy, single dose on day 7). Survival is monitored, and tumors are analyzed for immune cell infiltration [2] - For breast cancer nanocarrier study: Mice with subcutaneous 4T1 tumors receive intravenous injections of the nanocarrier loaded with Navoximod (dose equivalent to 5 mg/kg) and paclitaxel (5 mg/kg) once every 3 days for 4 cycles. Tumor volume is measured every 2 days, and tissues are collected for immune cell profiling [3] |
| Toxicity/Toxicokinetics |
- In murine studies, Navoximod at therapeutic doses (100 mg/kg oral, 5 mg/kg in nanocarrier) shows no significant systemic toxicity, with no abnormal changes in body weight or major organ histology [2,3]
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| References |
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| Additional Infomation |
- Navoximod is a small-molecule IDO pathway inhibitor that blocks tryptophan catabolism, thereby reversing IDO-mediated immunosuppression in the tumor microenvironment. It enhances anti-tumor immunity by promoting T cell activation and reducing immune-suppressive cells [1,2,3]
- The combination of Navoximod with chemo-radiation or chemotherapy (e.g., paclitaxel) exhibits synergistic anti-tumor effects by combining direct cytotoxicity with immune activation [2,3] Navoximod is under investigation in clinical trial NCT02048709 (Indoleamine 2,3-Dioxygenase (IDO) Inhibitor in Advanced Solid Tumors). Navoximod is an orally available inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), with potential immunomodulating and antineoplastic activities. Upon administration, navoximod targets and binds to IDO1, a cytosolic enzyme responsible for the oxidation of the essential amino acid tryptophan into kynurenine. By inhibiting IDO1 and decreasing kynurenine in tumor cells, this agent increases tryptophan levels, restores the proliferation and activation of various immune cells, including dendritic cells (DCs), natural killer (NK) cells, and T-lymphocytes, and causes a reduction in tumor-associated regulatory T-cells (Tregs). Activation of the immune system, which is suppressed in many cancers, may induce a cytotoxic T-lymphocyte (CTL) response against the IDO1-expressing tumor cells. IDO1 is overexpressed by a variety of tumor cell types and plays an important role in immunosuppression. Tryptophan depletion is associated with immunosuppression caused by T-cell suppression. |
| Molecular Formula |
C18H21FN2O2
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| Molecular Weight |
316.38
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| Exact Mass |
316.158
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| Elemental Analysis |
C, 68.34; H, 6.69; F, 6.01; N, 8.85; O, 10.11
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| CAS # |
1402837-78-8
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| Related CAS # |
IDO-IN-5;1402837-79-9;IDO-IN-6;1402837-76-6;IDO-IN-8;1402837-77-7
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| PubChem CID |
70914230
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| Appearance |
White to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
555.4±35.0 °C at 760 mmHg
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| Flash Point |
289.7±25.9 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.683
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| LogP |
1.28
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
23
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| Complexity |
416
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| Defined Atom Stereocenter Count |
2
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| SMILES |
FC1=C([H])C([H])=C([H])C2C3=C([H])N=C([H])N3[C@]([H])(C=21)C([H])([H])[C@]([H])(C1([H])C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])O[H])O[H]
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| InChi Key |
YGACXVRLDHEXKY-LHPNLFKDSA-N
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| InChi Code |
InChI=1S/C18H21FN2O2/c19-14-3-1-2-13-16-9-20-10-21(16)15(18(13)14)8-17(23)11-4-6-12(22)7-5-11/h1-3,9-12,15,17,22-23H,4-8H2/t11?,12?,15-,17+/m0/s1
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| Chemical Name |
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (9.48 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3 mg/mL (9.48 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 3 mg/mL (9.48 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (7.90 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 2.5 mg/mL (7.90 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 6: ≥ 0.5 mg/mL (1.58 mM) (saturation unknown) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1608 mL | 15.8038 mL | 31.6076 mL | |
| 5 mM | 0.6322 mL | 3.1608 mL | 6.3215 mL | |
| 10 mM | 0.3161 mL | 1.5804 mL | 3.1608 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 Figure 1n vitrobiological activities of PEG2k-Fmoc-NLG.Nat Commun. 2016 Nov 7;7:13443. |
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 In vivobiological activities of PEG2k-Fmoc-NLG.Nat Commun. 2016 Nov 7;7:13443. |
 IDO-blockade synergizes with chemo-radiation therapy. |
 Inhibition or absence of IDO triggers widespread complement deposition in tumors after chemo-radiation therapy.J Immunother Cancer. 2014 Jul 7;2:21. |
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 Dose-dependent antitumor efficacy ofNLG919.Int J Immunopathol Pharmacol.2017 Sep;30(3):215-226. |
 Combinatorial treatment withNLG919and paclitaxel.J Immunother Cancer. 2014 Jul 7;2:21.
NLG919increased the sensitivity of B16-F10 cells to paclitaxel after treatment with IFN-γ.Int J Immunopathol Pharmacol.2017 Sep;30(3):215-226. |
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