MSA-2 is an orally available non-nucleotide interferon gene stimulator (STING) agonist, with EC50 values of 8.3μM and 24μM for human STING subtypes WT and HAQ, respectively[1]. MSA-2 exhibits higher potency in the acidic tumor microenvironment, where the small molecule undergoes non-covalent dimerization to form a bioactive ligand[2]. MSA-2 in solution exists as monomers and noncovalent dimers in an equilibrium that holds a strong tendency towards the monomeric state[3].
In vitro, MSA-2 (20-50 μM) treatment of porcine PK-15 cells infected with Seneca Valley virus (SVV) for 24 hours dose-dependently inhibited SVV replication in the cells, activated the STING signaling pathway, and induced the expression of cytokines IFN-β, IL-6, and TNF-α[4]. MSA-2 (10, 50 μM) treatment of RAW264.7 cells for 24 hours increased intracellular IFN-β levels[5]. MSA-2 (25μM) treatment of human monocytes for 20 hours eliminated LPS-induced IL-10 and IL-19 production, while IL-1β and TNF-α were not inhibited[6].
In vivo, MSA-2 (p.o. 60 mg/kg or s.c. 50 mg/kg) treatment of mice with colon cancer models effectively inhibited tumor growth and increased levels of cytokines IFN-β, IL-6, and TNF-α in tumor cells[1]. MSA-2 (150 μg) administered intrathecally to mice with colon cancer and melanoma models significantly inhibited tumor growth, improved survival rates, enhanced the infiltration and activity of cytotoxic T cells in tumors, and contributed to tumor regression[5].
References:
[1] Pan B S, Perera S A, Piesvaux J A, et al. An orally available non-nucleotide STING agonist with antitumor activity[J]. Science, 2020, 369(6506): eaba6098.
[2] Liu J, Huang X, Ding J. Identification of MSA-2: An oral antitumor non-nucleotide STING agonist[J]. Signal Transduction and Targeted Therapy, 2021, 6(1): 18.
[3] Yang J, Luo Z, Ma J, et al. A next-generation STING agonist MSA-2: From mechanism to application[J]. Journal of Controlled Release, 2024, 371: 273-287.
[4] Lin H, Zhang R, Xiang H, et al. A Non-Nucleotide STING Agonist MSA-2 Synergized with Manganese in Enhancing STING Activation to Elicit Potent Anti-RNA Virus Activity in the Cells[J]. Viruses, 2023, 15(11): 2138.
[5] Wang M, Cai Y, He T, et al. Antitumor Effect of Platinum-Modified STING Agonist MSA-2[J]. ACS omega, 2024, 9(2): 2650-2656.
Kabelitz D, Zarobkiewicz M, Heib M, et al. Signal strength of STING activation determines cytokine plasticity and cell death in human monocytes[J]. Scientific Reports, 2022, 12(1): 17827.
MSA-2是一种口服非核苷酸干扰素基因刺激因子（STING）激动剂，对人的STING亚型WT和HAQ的EC50分别为8.3和24μM[1]。MSA-2在酸性肿瘤微环境中表现出更高的效力，其中小分子发生非共价二聚化形成生物活性配体[2]。MSA-2在溶液中以单体和非共价二聚体的形式存在，且该平衡强烈偏向于单体状态[3]。
在体外，MSA-2（20-50μM）处理塞内卡谷病毒（SVV）感染后的猪PK-15细胞24 h，剂量依赖性地抑制了细胞中SVV的复制，激活了STING信号通路，诱导了IFN-β、IL-6和TNF-α细胞因子的表达[4]。MSA-2（10、50μM）处理RAW264. 7细胞24h，均升高了胞内IFN-β的水平[5]。MSA-2（25μM）处理人单核细胞20h，发现脂多糖（LPS）诱导的IL-10和IL-19的产生被消除，而IL-1β和TNF-α不受抑制[6]。
在体内，MSA-2（p.o. 60 mg/kg or s.c. 50 mg/kg）治疗结肠癌模型小鼠，有效抑制了肿瘤生长，升高了肿瘤细胞中IFN-β、IL-6和TNF-α细胞因子的水平[1]。MSA-2（150μg）通过鞘内注射治疗结肠癌模型和黑色素瘤模型小鼠，均显著抑制了肿瘤生长并提高了生存率，增强了肿瘤中细胞毒性T细胞的浸润和活性，有助于诱导肿瘤消退[5]。