TAK-676 (TAK676) is a novel STING agonist that is able to trigger the activation of STING signaling pathway and type I interferons. It is also a modulator of immune system, resulting complete regressions and durable memory T-cell immunity. TAK-676 can promote durable IFN-dependent antitumor immunity.
Physicochemical Properties
| Molecular Formula | C21H20F2N8NA2O10P2S2 |
| Molecular Weight | 754.484971046448 |
| Exact Mass | 753.998 |
| CAS # | 2553413-93-5 |
| Related CAS # | Dazostinag;2553413-86-6 |
| PubChem CID | 165412584 |
| Appearance | White to off-white solid powder |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 19 |
| Rotatable Bond Count | 2 |
| Heavy Atom Count | 47 |
| Complexity | 1300 |
| Defined Atom Stereocenter Count | 8 |
| SMILES | S=P1([O-])OC[C@@H]2[C@H]([C@H]([C@H](N3C=NC4C(N)=NC=NC3=4)O2)F)OP(=O)(OC[C@@H]2[C@H]([C@H]([C@H](N3C=C(C4C(NC=NC3=4)=O)F)O2)O1)O)[S-].[Na+].[Na+] |
| InChi Key | DSMDURFDSXGNPW-RLKXMDTLSA-L |
| InChi Code | InChI=1S/C21H22F2N8O10P2S2.2Na/c22-7-1-30(17-10(7)19(33)28-5-26-17)21-15-13(32)8(38-21)2-36-42(34,44)40-14-9(3-37-43(35,45)41-15)39-20(11(14)23)31-6-29-12-16(24)25-4-27-18(12)31;;/h1,4-6,8-9,11,13-15,20-21,32H,2-3H2,(H,34,44)(H,35,45)(H2,24,25,27)(H,26,28,33);;/q;2*+1/p-2/t8-,9-,11-,13-,14-,15-,20-,21-,42?,43?;;/m1../s1 |
| Chemical Name | disodium;7-[(1R,6R,8R,9R,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9-fluoro-18-hydroxy-12-oxido-3-oxo-12-sulfanylidene-3-sulfido-2,4,7,11,13,16-hexaoxa-3λ5,12λ5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-5-fluoro-3H-pyrrolo[2,3-d]pyrimidin-4-one |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| ln Vitro | In THP1-Dual human AML cells and CT26.WT cells, dazostinag disodium (1.1, 3.3, and 10 μM; 2 h) dose-dependently activates the STING-TBK1-IRF3 pathway, however it is significantly dependent on STING expression[1]. In vitro immune cell activation activity of disodium (0-1 μM; 24 h) on mouse BM-derived dendritic cells is dose-dependent[1]. Dendritic cells (DC), natural killer (NK) cells, and T cells are all activated more readily by dazostigman disodium (0-1 μM; 24 h); activation EC50s are 1.27 μM (MoDC), 0.32 μM (BMDC), 0.271 μM (NK), 0.216 μM (CD8+), and 0.249 μM (CD4+) at 24 h, respectively[1]. |
| ln Vivo | Dazostinag disodium (0.025–2 mg/kg; IV; single dose) is more exposed in mice's tumors, has dose-proportional pharmacokinetics in plasma, and is well tolerated[1]. BALB/c mice with A20 syngeneic tumors/CT26.WT syngeneic tumors mode demonstrate anti-tumor function when administered with dazostinag disodium (1 mg/kg/d, 2 mg/kg/d; iv; 13 d)[1]. |
| Cell Assay |
Western Blot Analysis[1] Cell Types: THP1-Dual human AML cells and CT26.WT cells Tested Concentrations: 1.1, 3.3, 10 μM Incubation Duration: 2 hrs (hours) Experimental Results: Increased pTBK1, pSTING, pIRF3 protein level in a dose-dependent manner. Not induced the phosphorylation of pTBK1 (S172) or pIRF3 (S396) in the absence of STING expression. |
| Animal Protocol |
Animal/Disease Models: balb/c (Bagg ALBino) mouse bearing A20 syngeneic tumors/CT26. WT syngeneic tumors model[1] Doses: 1 or 2 mg/kg/day Route of Administration: intravenous (iv) injection; for 3, 6, 9, 12 day, respectively Experimental Results: Resulted in significant T cell–dependent in vivo antitumor activity. Induced dose- dependent cytokine responses and increased the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. |
| References |
[1]. TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies. Cancer Research Communications. 2022. 2(6): 489–502. |
| Additional Infomation | Dazostinag Disodium is the disodium salt form of dazostinag, an agonist of the stimulator of interferon genes protein (STING; transmembrane protein 173; TMEM173), with potential immunoactivating and antineoplastic activities. Upon intravenous administration, dazostinag targets and binds to STING and activates the STING pathway in immune cells in the tumor microenvironment (TME). This leads to the production of pro-inflammatory cytokines, including interferons (IFNs), enhances the cross-presentation of tumor-associated antigens (TAAs) by dendritic cells (DCs), and induces a cytotoxic T-lymphocyte (CTL)-mediated immune response against cancer cells. STING, a transmembrane protein that activates immune cells in the TME, plays a key role in the activation of the innate immune system. |
Solubility Data
| 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 |
| 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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3254 mL | 6.6270 mL | 13.2540 mL | |
| 5 mM | 0.2651 mL | 1.3254 mL | 2.6508 mL | |
| 10 mM | 0.1325 mL | 0.6627 mL | 1.3254 mL |