The discovery of potent small molecule cyclic urea activators of STING

Eur J Med Chem. 2022 Feb 5:229:114087. doi: 10.1016/j.ejmech.2021.114087. Epub 2021 Dec 31.

Abstract

STING mediates innate immune responses that are triggered by the presence of cytosolic DNA. Activation of STING to boost antigen recognition is a therapeutic modality that is currently being tested in cancer patients using nucleic-acid based macrocyclic STING ligands. We describe here the discovery of 3,4-dihydroquinazolin-2(1H)-one based 6,6-bicyclic heterocyclic agonists of human STING that activate all known human variants of STING with high potency.

Keywords: Immune oncology; Innate immunity; Interferon; STING; cGAS.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cytosol / chemistry
  • DNA / chemistry
  • Haplorhini
  • Humans
  • Immunity, Innate / drug effects*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / drug therapy*
  • Protein Binding
  • Signal Transduction
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Membrane Proteins
  • STING1 protein, human
  • Small Molecule Libraries
  • DNA