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diABZI STING agonist-1 is a novel, potent and selective STING (stimulator of interferon genes) receptor agonist, with an EC50s of 130 nM for human PBMCs.
| Targets |
Stimulator of interferon genes (STING)
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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].
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| ln Vivo |
In vivo, STING-dependent activation of type I interferons and proinflammatory cytokines is induced by diABZI STING agonist-1 (subcutaneous injection; 2.5 mg/kg) [1]. ? DiABZI STING Agonist-1 (iv; 3 mg/kg) produced systemic concentrations higher than the half-maximum effective concentration (EC50) of mouse STING (200 ng/ml) and showed systemic exposure with a half-life of 1.4 hours [1]. Significantly reducing tumor development and improving survival was the effect of diABZI STING Agonist-1 (iv; 1.5 mg/kg; Days 1, 4, and 8; Day 43). [1].
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| Enzyme Assay |
To identify any potential off-target liabilities early on, an affinity enrichment-based chemoproteomics strategy was applied to compound 2 (diABZI STING agonist-1). Compound 5, an active analogue containing a primary amine functionality, was covalently immobilized on sepharose beads and was used to affinity-capture potential target proteins from a THP1 cell lysate. Pull-down experiments were performed in the absence of free compound 2 to delineate target proteins from background or in the presence of compound 2 over a range of concentrations. All proteins captured by the beads under the different conditions were eluted and subsequently quantified by isotope tagging of tryptic peptides followed by LC–MS/MS analysis to establish a competition-binding curve and determine a half-maximal inhibition (IC50) value. The IC50 values obtained in these experiments represent a measure of target affinity, but are also affected by the affinity of the target for the bead-immobilized ligand. The latter effect can be deduced by determining the depletion of the target proteins by the beads, such that apparent dissociation constants can be determined, which are largely independent from the bead ligand (see Supplementary Methods for details). Notably, only two proteins were captured and competed in a dose-dependent manner within a 1,000-fold window, namely STING and orosomucoid1 (ORM1, alpha-1-acid glycoprotein 1 precursor). The mean value for STING was determined as 1.6 nM, demonstrating high potency of compound 2 on the target protein not only in an artificial biochemical assay system using truncated protein but also against the full-length endogenous human protein. The mean value of the only identified off-target protein, ORM1, was determined as 79 nM giving a comfortable selectivity window of approximately 40-fold. ORM1 is an acute phase reactant, an abundant plasma protein with known drug binding properties, and is known to be expressed in monocytes.[1]
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| 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: The secretion of IFNβ, IL-6, TNF and CXCL1 was activated in wild-type mice, but Sting None in −/− mice. BALB/c mouse colorectal tumor syngeneic mouse model (CT-26) [1] Doses: 3 mg/kg Route of Administration: intravenous (iv) (iv)injection; 3 mg/kg Experimental Results: Half-life is 1.4 hrs (hrs (hours)), systemic concentration is greater than the EC50 of mouse STING (200 ng/ 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; 1.5 mg/kg; 43-day Experimental Results: Dramatically inhibited tumor growth and improved survival rate. |
| 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.[1]
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| Molecular Formula |
C42H51N13O7
|
|---|---|
| Molecular Weight |
849.937247514725
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| Exact Mass |
849.403
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| CAS # |
2138299-33-7
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| Related CAS # |
diABZI STING agonist-1 trihydrochloride;2138299-34-8;diABZI STING agonist-1 (Tautomerism);2138498-18-5
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| PubChem CID |
131986624
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| Appearance |
Typically exists as White to off-white solids
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| LogP |
1.9
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
18
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| Heavy Atom Count |
62
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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
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| InChi Key |
JGLMVXWAHNTPRF-CMDGGOBGSA-N
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| InChi Code |
InChI=1S/C42H51N13O7/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)/b9-8+
|
| 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
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| Synonyms |
diABZI STING agonist-1; 2138498-18-5; diABZI STING agonist-3; 2138299-33-7; STING agonist 3; diABZI STING agonist-1 (Tautomerism); diABZI STING agonist-1 Tautomerism; L7DUG75C36;
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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 and light. |
| 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 : ~100 mg/mL (~117.66 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.5 mg/mL (4.12 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 35.0 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: ≥ 3.5 mg/mL (4.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 35.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1766 mL | 5.8828 mL | 11.7655 mL | |
| 5 mM | 0.2353 mL | 1.1766 mL | 2.3531 mL | |
| 10 mM | 0.1177 mL | 0.5883 mL | 1.1766 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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