Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route

J Med Chem. 2021 May 27;64(10):6902-6923. doi: 10.1021/acs.jmedchem.1c00374. Epub 2021 May 17.


Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.

MeSH terms

  • Administration, Intravenous
  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Half-Life
  • Humans
  • Immunotherapy
  • Membrane Proteins / agonists*
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Docking Simulation
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Nucleotides, Cyclic / chemistry*
  • Nucleotides, Cyclic / metabolism
  • Nucleotides, Cyclic / therapeutic use
  • Phosphates / chemistry
  • Pyrimidines / chemistry*
  • Rats
  • Structure-Activity Relationship
  • Transplantation, Heterologous


  • Membrane Proteins
  • Nucleotides, Cyclic
  • Phosphates
  • Pyrimidines
  • STING1 protein, human
  • phosphorodithioic acid