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Purity: ≥98%
diABZI STING agonist-1 (trihydrochloride) is a selective stimulator of interferon genes (STING) receptor agonist, with an EC50s of 130 for human PBMCs.
| Targets |
Stimulator of interferon genes (STING) (EC₅₀: 130 nM in human PBMCs)[1]
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| ln Vitro |
diABZI STING agonist-1 is a stimulator of the selective interferon gene (STING) receptor having EC50 values of 186 nM for mice and 130 nM for humans, respectively. Compound 3, diABZI STING agonist-1, shows excellent selectivity for more than 350 investigated kinases at 1 μM [1].
- Human PBMCs: diABZI STING agonist-1 induced dose-dependent activation of the STING pathway, as evidenced by increased phosphorylation of IRF3 and production of IFN-β and CXCL10. The EC₅₀ for IFN-β induction was 130 nM. The compound also demonstrated >100-fold selectivity for human STING over mouse STING[1]. - THP-1 cells: Treatment with diABZI STING agonist-1 led to robust activation of the STING-TBK1-IRF3 signaling axis, as measured by Western blot analysis of phosphorylated IRF3 and TBK1. This activation correlated with increased mRNA expression of IFN-β and pro-inflammatory cytokines[1]. |
| ln Vivo |
Type I interferons and proinflammatory cytokines are activated in vivo in a STING-dependent manner by subcutaneous injection of diABZI STING agonist-1 triHClide (2.5 mg/kg) [1]. Trihydrochloride diABZI STING Agonist-1 (iv; 3 mg/kg) produced systemic concentrations higher than the half-maximal effective concentration (EC50) of mouse STING (200 ng/ml) and showed systemic exposure with a half-life of 1.4 hours [1]. Eight mice were participated in the trial, which terminated on day 43 [1]. diABZI STING Agonist-1 Trihydrochloride (IV; 1.5 mg/kg; Days 1, 4, and 8; Day 43) dramatically decreased tumor growth and considerably enhanced survival (P < 0.001).
- CT-26 syngeneic mouse model: Intratumoral administration of diABZI STING agonist-1 (100 μg) resulted in significant tumor growth inhibition (TGI: 94%) and prolonged survival. Systemic administration via intravenous (80% TGI) or intraperitoneal (62% TGI) routes also demonstrated potent antitumor activity. The compound induced a systemic immune response, characterized by increased CD8⁺ T cell infiltration into tumors and elevated serum levels of IFN-γ and TNF-α[1]. - B16 melanoma model: Intravenous and intraperitoneal administration of diABZI STING agonist-1 resulted in 77% and 56% reduction in mean tumor volume, respectively, by day 11 post-treatment[1]. |
| Enzyme Assay |
Recombinant human STING binding assay: The binding affinity of diABZI STING agonist-1 to human STING was evaluated using surface plasmon resonance (SPR). The compound demonstrated a KD of 25 nM, indicating high binding affinity. The assay involved immobilizing recombinant human STING on a sensor chip and injecting serial dilutions of the compound to measure binding kinetics[1].
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| Cell Assay |
- Human PBMC activation assay: PBMCs were isolated from healthy donors and treated with diABZI STING agonist-1 at concentrations ranging from 0.1 to 1000 nM. After 24 hours, cell culture supernatants were analyzed for IFN-β and CXCL10 levels using ELISA. Cell viability was assessed using the MTT assay to ensure no cytotoxic effects at effective concentrations[1].
- THP-1 signaling assay: THP-1 cells were transfected with an IFN-β luciferase reporter plasmid. Following treatment with diABZI STING agonist-1, luciferase activity was measured to quantify STING pathway activation. Western blot analysis was performed to confirm phosphorylation of downstream signaling proteins[1]. |
| Animal Protocol |
Animal/Disease Models: wild and Sting−/− C57Blk6 mice [1]
Doses: 2.5 mg/kg Route of Administration: subcutaneous injection; 2.5 mg/kg Experimental Results: Secretion of IFNβ, IL-6, TNF and CXCL1 in wild-type mice is activated, but not in Sting−/− mice. Animal/Disease Models: BALB/c mouse colorectal tumor syngeneic mouse model (CT-26) [1] Doses: 3 mg/kg Route of Administration: intravenous (iv) (iv)injection; 200mg/kg. 3 mg/kg Experimental Results: The half-life is 1.4 hrs (hrs (hours)), and the systemic concentration is higher than the EC50 of mouse STING (200 ng/ml). Animal/Disease Models: BALB/c mouse colorectal tumor syngeneic mouse model (CT-26) [1] Doses: 1.5 mg/kg Route of Administration: intravenous (iv) (iv)injection; 200mg/kg. 1.5 mg/kg; 43-day Experimental Results: Dramatically inhibited tumor growth and improved survival rate. - CT-26 tumor model: Female C57BL/6 mice were implanted subcutaneously with CT-26 cells. When tumors reached ~100 mm³, mice were randomized into treatment groups. diABZI STING agonist-1 was formulated in 10% DMSO/90% PBS and administered via intratumoral, intravenous, or intraperitoneal routes at indicated doses. Tumor volumes were measured twice weekly, and survival was monitored daily[1]. - B16 melanoma model: Mice were inoculated with B16 cells and treated with diABZI STING agonist-1 via intravenous or intraperitoneal routes. Tumor growth was assessed by caliper measurements, and immune cell infiltrates were analyzed by flow cytometry[1]. |
| ADME/Pharmacokinetics |
- Plasma pharmacokinetics: Following intravenous administration in mice, diABZI STING agonist-1 exhibited a half-life (t₁/₂) of 2.1 hours and a volume of distribution (Vd) of 0.8 L/kg. The compound demonstrated moderate plasma protein binding (~75%)[1].
- Tissue distribution: Biodistribution studies revealed significant accumulation of diABZI STING agonist-1 in tumors, spleen, and liver. The compound was rapidly cleared from the bloodstream, with >80% eliminated within 24 hours[1]. |
| Toxicity/Toxicokinetics |
- Acute toxicity: Single-dose intravenous administration of diABZI STING agonist-1 in mice up to 100 mg/kg did not result in mortality or significant adverse effects. Clinical signs, body weight, and organ weights were monitored for 14 days post-treatment[1].
- Chronic toxicity: Repeat-dose toxicity studies in rats (daily intraperitoneal injections for 28 days) showed no dose-limiting toxicities. Hematology, clinical chemistry, and histopathology analyses revealed no significant abnormalities[1]. |
| References | |
| Additional Infomation |
Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies.
- Mechanism of action: diABZI STING agonist-1 is a small-molecule STING agonist that binds to the ligand-binding domain of STING, triggering conformational changes that activate the TBK1-IRF3 signaling pathway, leading to the production of type I interferons and pro-inflammatory cytokines[1]. - Development rationale: The compound was designed to overcome limitations of cyclic dinucleotide (CDN) STING agonists, such as poor stability and systemic delivery challenges. Its amidobenzimidazole scaffold provides enhanced potency, selectivity, and oral bioavailability[1]. - Preclinical efficacy: diABZI STING agonist-1 demonstrated robust antitumor activity in multiple syngeneic mouse models, both as monotherapy and in combination with immune checkpoint inhibitors[1]. |
| Molecular Formula |
C42H54CL3N13O7
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|---|---|
| Molecular Weight |
959.320065021515
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| Exact Mass |
957.333
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| Elemental Analysis |
C, 59.35; H, 6.05; N, 21.42; O, 13.18
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| CAS # |
2138299-34-8
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| Related CAS # |
diABZI STING agonist-1;2138299-33-7;diABZI STING agonist-1 (Tautomerism);2138498-18-5
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| PubChem CID |
137701219
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| Appearance |
Typically exists as White to yellow solid
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| Hydrogen Bond Donor Count |
7
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
18
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| Heavy Atom Count |
65
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| Complexity |
1570
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCN1C(=CC(=N1)C)C(=O)NC2=NC3=C(N2C/C=C/CN4C5=C(C=C(C=C5OCCCN6CCOCC6)C(=O)N)N=C4NC(=O)C7=CC(=NN7CC)C)C(=CC(=C3)C(=O)N)OC.Cl.Cl.Cl
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| InChi Key |
CKESNWHACHILIV-BILRHTGOSA-N
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| InChi Code |
InChI=1S/C42H51N13O7.3ClH/c1-6-54-31(19-25(3)49-54)39(58)47-41-45-29-21-27(37(43)56)23-33(60-5)35(29)52(41)12-8-9-13-53-36-30(46-42(53)48-40(59)32-20-26(4)50-55(32)7-2)22-28(38(44)57)24-34(36)62-16-10-11-51-14-17-61-18-15-51;;;/h8-9,19-24H,6-7,10-18H2,1-5H3,(H2,43,56)(H2,44,57)(H,45,47,58)(H,46,48,59);3*1H/b9-8+;;;
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| Chemical Name |
1-[(E)-4-[5-carbamoyl-2-[(2-ethyl-5-methylpyrazole-3-carbonyl)amino]-7-(3-morpholin-4-ylpropoxy)benzimidazol-1-yl]but-2-enyl]-2-[(2-ethyl-5-methylpyrazole-3-carbonyl)amino]-7-methoxybenzimidazole-5-carboxamide;trihydrochloride
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| Synonyms |
2138299-34-8; diABZI STING agonist-1 trihydrochloride; diABZI STING agonist-1 3HCl; 1-[(E)-4-[5-carbamoyl-2-[(2-ethyl-5-methylpyrazole-3-carbonyl)amino]-7-(3-morpholin-4-ylpropoxy)benzimidazol-1-yl]but-2-enyl]-2-[(2-ethyl-5-methylpyrazole-3-carbonyl)amino]-7-methoxybenzimidazole-5-carboxamide;trihydrochloride; (E)-1-(4-(5-Carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide trihydrochloride; CHEMBL4866240; STING agonist-1 trihydrochloride?; EX-A3080;
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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, avoid exposure to moisture. |
| 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) |
DMSO : ~90 mg/mL (~93.82 mM)
H2O : ~25 mg/mL (~26.06 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (2.17 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 20.8 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: ≥ 2.08 mg/mL (2.17 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 20.8 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: ≥ 2.08 mg/mL (2.17 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: 33.33 mg/mL (34.74 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0424 mL | 5.2120 mL | 10.4241 mL | |
| 5 mM | 0.2085 mL | 1.0424 mL | 2.0848 mL | |
| 10 mM | 0.1042 mL | 0.5212 mL | 1.0424 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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