Stimulator of interferon genes (STING) (EC₅₀: 130 nM in human PBMCs)[1]

diABZI STING agonist-1 是选择性干扰素基因 (STING) 受体的刺激剂，对小鼠的 EC50 值分别为 186 nM，对人类的 EC50 值分别为 130 nM。化合物 3（diABZI STING agonist-1）在 1 μM 浓度下对超过 350 种研究的激酶表现出优异的选择性 [1]。

---

- 人外周血单个核细胞 (PBMCs)：diABZI STING agonist-1 剂量依赖性激活STING通路，表现为IRF3磷酸化增加以及IFN-β和CXCL10生成增多。IFN-β诱导的EC₅₀为130 nM。该化合物对人STING的选择性超过小鼠STING 100倍以上[1]。
- THP-1细胞：diABZI STING agonist-1 处理后显著激活STING-TBK1-IRF3信号轴，通过Western blot检测到磷酸化IRF3和TBK1水平升高。同时，IFN-β和促炎细胞因子的mRNA表达显著上调[1]。

通过皮下注射 diABZI STING 激动剂-1 三氯化物 (2.5 mg/kg)，I 型干扰素和促炎细胞因子以 STING 依赖性方式在体内被激活 [1]。三盐酸盐 diABZI STING Agonist-1（静脉注射；3 mg/kg）产生的全身浓度高于小鼠 STING（200 ng/ml）的半最大有效浓度（EC50），并且显示出全身暴露，半衰期为 1.4 小时。 1]。 8 只小鼠参与了试验，试验于第 43 天结束[1]。 diABZI STING Agonist-1 TriHClide（IV；1.5 mg/kg；第 1、4 和 8 天；第 43 天）显着降低肿瘤生长并显着提高生存率（P < 0.001）。

---

- CT-26同基因小鼠模型：瘤内注射diABZI STING agonist-1 (100 μg) 显著抑制肿瘤生长 (TGI: 94%) 并延长生存期。静脉 (80% TGI) 或腹腔 (62% TGI) 全身给药同样显示强效抗肿瘤活性。该化合物诱导系统性免疫应答，表现为肿瘤内CD8⁺ T细胞浸润增加以及血清IFN-γ和TNF-α水平升高[1]。
- B16黑色素瘤模型：静脉和腹腔注射diABZI STING agonist-1后，第11天平均肿瘤体积分别减少77%和56%[1]。

重组人STING结合实验：采用表面等离子体共振 (SPR) 评估diABZI STING agonist-1与人STING的结合亲和力，KD为25 nM，表明高亲和力结合。实验将重组人STING固定在传感器芯片上，注射系列稀释的化合物以测量结合动力学[1]。

- 人PBMC激活实验：从健康供体分离PBMC，用0.1至1000 nM的diABZI STING agonist-1处理24小时，ELISA检测培养上清中IFN-β和CXCL10水平。MTT法评估细胞活力，确认有效浓度下无细胞毒性[1]。
- THP-1信号实验：THP-1细胞转染IFN-β荧光素酶报告质粒，处理后检测荧光素酶活性以量化STING通路激活。Western blot验证下游信号蛋白磷酸化[1]。

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].

- 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].

- 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].

[1]. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature. 2018 Dec;564(7736):439-443.

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].

C42H54CL3N13O7

959.320065021515

957.333

C, 59.35; H, 6.05; N, 21.42; O, 13.18

2138299-34-8

diABZI STING agonist-1;2138299-33-7;diABZI STING agonist-1 (Tautomerism);2138498-18-5

137701219

Typically exists as White to yellow solid

247Ų

7

12

18

65

1570

0

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

CKESNWHACHILIV-BILRHTGOSA-N

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+;;;

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

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;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~90 mg/mL (~93.82 mM)
H2O : ~25 mg/mL (~26.06 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (2.17 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.08 mg/mL (2.17 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

---

View More

配方 3 中的溶解度: ≥ 2.08 mg/mL (2.17 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

配方 4 中的溶解度: 33.33 mg/mL (34.74 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。