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.