E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity

ChemMedChem. 2021 Jun 7;16(11):1740-1743. doi: 10.1002/cmdc.202100068. Epub 2021 Feb 25.


A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766, exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.

Keywords: STING agonists; cyclic dinucleotides; drug design; immuno-oncology; macrocycles.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Humans
  • Interferons / agonists*
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology


  • Antineoplastic Agents
  • Macrocyclic Compounds
  • Interferons