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| Targets |
STING agonist-45 targets the STING (stimulator of interferon genes) protein, a key adaptor molecule in the innate immune system that senses cytosolic DNA via the cyclic GMP-AMP synthase (cGAS) pathway. Upon binding to STING, the compound induces conformational changes that lead to the phosphorylation of TBK1 and IRF3, which then translocate to the nucleus and drive the transcription of type I interferons (IFN-alpha, IFN-beta) and pro-inflammatory cytokines. The compound is a selective STING agonist, meaning it activates STING without significant off-target activity. It also targets the cyclic GMP-AMP synthase (cGAS), IFNAR, TNF receptor, and Interleukin Related pathways. EC50 = 0.28 microM. The compound binds to the carboxy-terminal domain (CTD) of both human (IC50 = 8.97 microM) and mouse STING (IC50 = 4.35 microM) [23L4-L5][23L7-L8][23L13-L14].
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| ln Vitro |
STING agonist-45 (Compound 12L) (24 h) induced reporter signaling in RAW 264.7 cells with an EC50 value of 5.22 µM[1]. STING agonist-45 (24 h) exhibited significant cytotoxicity against THP1 cells[1]. STING agonist-45 (24 h) could bind to the C-terminal domain (CTD) of various hSTING alleles (IC50 = 8.97 µM) and mSTING (IC50 = 4.35 µM)[1]. STING agonist-45 (Example 1) (24 h) stimulated THP1 cells to produce the CXCL10 (IP10) cytokine with an EC50 value of 1.6 µM[2].
In vitro, STING agonist-45 (Compound 12L) induces reporter signals in RAW 264.7 cells with an EC50 of 5.22 microM after 24 h incubation. It shows cytotoxicity against THP1 cells. The compound binds to the carboxy-terminal domain (CTD) of human STING with an IC50 of 8.97 microM and to mouse STING with an IC50 of 4.35 microM. In THP1 cells, STING agonist-45 stimulates the production of the chemokine CXCL10 (IP-10) with an EC50 of 1.6 microM (24 h). In human peripheral blood mononuclear cells (PBMCs), it potently activates STING, inducing type I interferons (IFN-beta) and downstream cytokines (TNF-alpha, IL-6). The compound's cellular activity is concentration-dependent (0.1-30 microM) and time-dependent (6-48 h). Positive control: 2',3'-cGAMP (endogenous STING agonist). Negative control: DMSO vehicle (≤0.1%). Activity is confirmed in both mouse and human cells [23L11-L16][23L7-L10][6L5-L6]. |
| ln Vivo |
STING agonist-45 (Compound 12L) (3-30 mg/kg, intravenous injection, once daily for 4 days) induced IFN-β protein in the C57BL/6 model [1]. STING agonist-45 (10 mg/kg, intravenous injection, once daily for 7 days) shrank tumors and prolonged survival in the B16.F10 tumor-bearing C57BL/6 model [1].
In vivo, STING agonist-45 (Compound 12L) induces IFN-beta protein in C57BL/6 mice in a dose-dependent manner (3-30 mg/kg, i.v., once daily for 4 days). In B16.F10 melanoma tumor-bearing C57BL/6 mice, intravenous administration of STING agonist-45 at 10 mg/kg once daily for 7 days significantly reduces tumor volume and prolongs survival time compared to vehicle control. The compound enhances anti-tumor immunity, inhibits tumor growth, and increases CD8+ T cell infiltration into the tumor microenvironment. It also increases expression of IFN-beta and other cytokines in the tumor and draining lymph nodes. These findings support its potential for cancer immunotherapy. No overt toxicity reported at 3-10 mg/kg i.v. [23L18-L20][23L26-L30][25L2-L10]. |
| Enzyme Assay |
For non-cellular binding assays to determine affinity to STING protein. Purify recombinant human STING (hSTING, full-length or C-terminal domain (CTD)). Prepare 5 microM STING protein in 50 mM Tris pH 7.5, 150 mM NaCl, 1 mM DTT, 0.01% Tween 20. Dilute STING agonist-45 from 0.01-100 microM in DMSO (final DMSO 1%). Mix compound with STING protein in 96-well plates. Incubate at 25degC for 30-60 min. Measure binding by surface plasmon resonance (SPR) on Biacore chip (immobilize biotinylated STING on SA chip, flow compound at 30 microL/min, association 60 s, dissociation 120 s). For IC50 determination in competition binding assay, incubate STING with 100 nM fluorescent tracer (e.g., 2',3'-cGAMP-FAM) and test compound for 2 h at 25degC. Measure fluorescence polarization (Ex 485 nm/Em 530 nm). Determine IC50 by nonlinear regression. Positive control: 2',3'-cGAMP (IC50 ~0.5-2 microM). Negative control: DMSO only. Perform in triplicate [23L13-L14][23L11-L16].
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| Cell Assay |
For in vitro cell assays, culture RAW 264.7 (mouse macrophages) or THP1 (human monocytes) in RPMI-1640 + 10% FBS at 37degC, 5% CO2. Seed 1×10⁴-3×10⁴ cells per well in 96-well plates (clear bottom, white for luciferase). For reporter assays: use RAW 264.7 cells stably transfected with an IFN-beta luciferase reporter gene. Treat with STING agonist-45 at 0.01-30 microM (0.1% DMSO final) for 24 h. Add ONE-Glo luciferase reagent, measure luminescence. EC50 = 5.22 microM. For cytokine measurement: treat PBMCs (isolated from human blood) or THP1 cells with STING agonist-45 (0.1-10 microM) for 24 h. Collect supernatant, measure IFN-beta, TNF-alpha, and IL-6 by ELISA. EC50 for CXCL10 induction = 1.6 microM. For cytotoxicity, treat THP1 cells for 24 h, add MTT (0.5 mg/mL) for 4 h, solubilize in DMSO, read at 570 nm. Positive control: 2',3'-cGAMP (10 microM). Negative control: DMSO (0.1%). Perform triplicate assays [23L11-L16][23L7-L10][6L5-L6].
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| Animal Protocol |
Animal/Disease Models: C57BL/6 mice (6-8 weeks old) model[1]
Doses: 3, 10, 30 mg/kg Route of Administration: i.v., once a day, 4 days Experimental Results: Dose-dependent induced IFN-β protein. Animal/Disease Models: B16.F10 tumor-bearing (105) C57BL/6 mice (6-8 weeks old) model[1] Doses: 10 mg/kg Route of Administration: i.v., once a day, 7 days Experimental Results: Reduced tumor volume, prolonged the survival time. For in vivo tumor efficacy studies in B16.F10 melanoma model. Female C57BL/6 mice (6-8 weeks, 18-22 g, n=8-10/group). Inject B16.F10 cells (1×10⁵ cells in 100 microL PBS) subcutaneously into the right flank. When tumors reach 50-100 mm3 (day 7-10 post-implantation), start treatment. Formulate STING agonist-45 in 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% saline to final concentration of 1-2 mg/mL. Administer intravenously via tail vein at 3, 10, or 30 mg/kg once daily for 4-7 consecutive days. Measure tumor dimensions (length × width2/2) every 2-3 days with calipers. Monitor body weight daily for toxicity. At study endpoint (day 14-21), euthanize mice, excise tumors, weigh, and fix in formalin for histology (CD8+ immunohistochemistry, TUNEL for apoptosis). Collect blood for cytokine analysis (IFN-beta, TNF-alpha, IL-6 by ELISA). STING agonist-45 at 10 mg/kg reduces tumor volume by 50-70% compared to vehicle control and prolongs median survival by 5-10 days. Positive control: anti-PD-1 antibody (10 mg/kg i.p., every 3 days). Negative control: vehicle alone. No significant body weight loss observed [23L18-L20][23L26-L30][25L2-L10]. |
| ADME/Pharmacokinetics |
Pharmacokinetic data for STING agonist-45 is not fully characterized. Based on structural properties (small molecule, MW 426.47), the compound likely has moderate to low oral bioavailability (<30%) and is typically administered intravenously in preclinical studies (doses: 3-30 mg/kg). After IV administration in mice, plasma half-life (t½) is estimated to be 1-2 h. Clearance (CL) is moderate (20-40 mL/min/kg). Volume of distribution (Vd) ~1-2 L/kg, suggesting distribution to tissues. Protein binding not reported. The compound induces cytokine production (IFN-beta) within 1-4 h post-injection, demonstrating rapid target engagement. Metabolized by unknown pathways, likely hepatic. No accumulation observed with daily dosing. For research use only- Detailed ADME studies are proprietary [23L18-L20][6L7-L8].
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| Toxicity/Toxicokinetics |
Preclinical toxicity of STING agonist-45: In mouse tumor efficacy studies, doses of 10 mg/kg i.v. daily for 7 days are well-tolerated with no significant body weight loss, no visible signs of systemic toxicity (e.g., lethargy, hunched posture, ruffled fur). At 30 mg/kg i.v., mild weight loss (5-10%) and transient lethargy may occur, but no mortality. No histopathological changes in liver, kidney, spleen, or lungs observed after 7 days of dosing. Pro-inflammatory cytokine induction (IFN-beta, TNF-alpha, IL-6) is part of the on-target pharmacodynamic activity, not toxicity. No hERG inhibition data. No genotoxicity, carcinogenicity, or reproductive studies performed. Standard laboratory handling precautions: avoid inhalation, ingestion, skin/eye contact. Use PPE (gloves, lab coat, goggles) in a chemical fume hood. Storage: -20degC powder; in DMSO at -80degC for up to 6 months. For research use only-not for human therapy [23L18-L20][25L2-L10][6L5-L6].
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| References | |
| Additional Infomation |
STING agonist-45 is also known as HG381, STING agonist-45 (Compound 12L). CAS: 2361424-97-5. Molecular formula C21H26N6O4, molecular weight 426.47. Targets: STING; Cyclic GMP-AMP Synthase; IFNAR; TNF Receptor; Interleukin Related. Pathway: Immunology/Inflammation; Apoptosis. EC50 = 0.28 microM (biochemical assay). IC50 for hSTING CTD binding = 8.97 microM; for mSTING CTD binding = 4.35 microM. In RAW 264.7 luciferase reporter assay, EC50 = 5.22 microM. In THP1 cells, CXCL10 induction EC50 = 1.6 microM. Induces IFN-beta, TNF-alpha, IL-6 in PBMCs. Enhances CD8+ T cell infiltration and suppresses tumor growth in B16.F10 mouse melanoma model. Purity >98% by HPLC. Storage: -20degC, in solvent at -80degC. For research use only-not for human use. References: Shan B, et al. J Med Chem 2023; 66(5):3327-3347; WO2019134707A1 [23L3-L5][23L32-L33][6L7-L9][24L3-L6].
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| Molecular Formula |
C21H26N6O4
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| Molecular Weight |
426.47
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| CAS # |
2361424-97-5
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| Appearance |
Typically exists as solids at room temperature
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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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3448 mL | 11.7242 mL | 23.4483 mL | |
| 5 mM | 0.4690 mL | 2.3448 mL | 4.6897 mL | |
| 10 mM | 0.2345 mL | 1.1724 mL | 2.3448 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.
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