diABZI STING agonist-1 is an agonist of the stimulator of interferon genes (STING) pathway with EC50 values of 130nM in humans and 186nM in mice, respectively [1]. STING plays an important role in regulating the transcription of a large number of host defense genes (including type I IFN) and protecting cells from cancer development. diABZI STING agonist-1 demonstrated anti-tumor activity in mice with colon tumors [2].
In vitro, treatment of human NSCLC cell lines (H460 and A549) with diABZI STING agonist-1 (20nM) for 24, 48, and 72 hours significantly inhibited the proliferation of both cells. The inhibitory effect of diABZI STING agonist-1 combined with low-dose IR (2 Gy) on the proliferation of non-small cell lung cancer cells was closer to that of high-dose IR [2]. Treating melanoma cells with diABZI STING agonist-1 (21nM) in the culture medium for 24 hours will increase the phosphorylation levels of TBK1 and STING, and the phosphorylated STING will be located in the area near the nucleus. In addition, IRF3 was phosphorylated, indicating that the STING pathway was activated [3].
In vivo, a single subcutaneous injection of diABZI STING agonist-1 (2.5mg/kg/d) in mice caused a strong local inflammatory response and skin lesions, with elevated serum IL-10 levels. Systemic pretreatment with poly(I:C) in mice led to an exacerbated response to diABZI STING agonist-1, higher levels of systemic cytokines, more severe skin lesions, and delayed resolution of skin inflammation [4]. By treating OVX-induced osteoporosis mice with diABZI STING agonist-1 (0.5mg/kg; i.p.) for 3 times a week for 2 weeks, the concentrations of RANKL and CTX-I in serum and the RANKL/OPG ratio were significantly reduced. diABZI STING agonist-1 alleviates bone resorption induced by Ti particles and osteoporosis induced by ovarian ablation in vivo by inhibiting OC differentiation and function [5].
References:
[1] Ramanjulu J M, Pesiridis G S, Yang J, et al. Design of amidobenzimidazole STING receptor agonists with systemic activity[J]. Nature, 2018, 564(7736): 439-443.
[2] Xue A, Shang Y, Jiao P, et al. Increased activation of cGAS‐STING pathway enhances radiosensitivity of non‐small cell lung cancer cells[J]. Thoracic cancer, 2022, 13(9): 1361-1368.
[3] Chipurupalli S, Ganesan R, Dhanabal S P, et al. Pharmacological STING activation is a potential alternative to overcome drug-resistance in melanoma[J]. Frontiers in oncology, 2020, 10: 758.
[4] Pyclik M, Durslewicz J, Papinska J A, et al. STING agonist-induced skin inflammation is exacerbated with prior systemic innate immune activation[J]. International Journal of Molecular Sciences, 2023, 24(4): 4128.
[5] Huang Y, Zhang M, Zhang J, et al. diABZI and poly (I: C) inhibit osteoclastic bone resorption by inducing IRF7 and IFIT3[J]. Journal of Bone and Mineral Research, 2024, 39(8): 1132-1146.
diABZI STING agonist-1是干扰素基因刺激物（STING）途径的激动剂，其在人和小鼠中的EC50值分别为130nM 和186nM [1]。STING在调节大量宿主防御基因（包括I型IFN）的转录和保护细胞免受癌症发展中起重要作用。diABZI STING agonist-1在结肠肿瘤小鼠中显示出抗肿瘤活性[2]。
在体外，diABZI STING agonist-1（20nM）处理人NSCLC细胞系（H460和A549）24、48和72小时，两种细胞的增殖均受到明显抑制。diABZI STING agonist-1与低剂量的 IR（2Gy）联合使用对非小细胞肺癌细胞增殖的抑制效果更接近于高剂量IR的效果 [2]。将黑色素瘤细胞置于含有diABZI STING agonist-1（21nM）的培养基处理24小时，会促使TBK1和STING的磷酸化程度增加，并且磷酸化后的STING的定位会出现在细胞核附近区域。此外，IRF3发生磷酸化，这表明STING通路已被激活 [3] 。
在体内，diABZI STING agonist-1（2.5mg/kg/d）单次皮下注射小鼠，引起了强烈的局部炎症反应和皮肤病变，血清IL-10水平升高。用poly（I：C）全身预处理小鼠导致对diABZI STING agonist-1的反应加剧，全身细胞因子水平更高，皮肤病变更严重，皮肤炎症消退延迟 [4]。通过每周3次持续2周diABZI STING agonist-1（0.5mg/kg；i.p.）治疗OVX诱导的骨质疏松小鼠，显著降低了血清中RANKL、CTX-I的浓度和RANKL/OPG比值。diABZI STING agonist-1通过抑制OC分化和功能 ，在体内减轻Ti颗粒诱导的骨质溶解和卵巢切除诱导的骨质疏松症中的骨丢失 [5]。