MSA-2 (Synonyms: 5,6-dimethoxy-γ-oxo-benzobthiophene-2-Butanoic Acid)

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.