Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic

Science. 2020 Aug 21;369(6506):993-999. doi: 10.1126/science.abb4255.

Abstract

Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic that induces the same "closed" conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • B7-H1 Antigen / metabolism
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / pharmacology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Crystallography, X-Ray
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Humans
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Nucleotides, Cyclic / chemistry
  • Nucleotides, Cyclic / pharmacology*
  • Protein Conformation / drug effects

Substances

  • Antineoplastic Agents
  • B7-H1 Antigen
  • Membrane Proteins
  • Nucleotides, Cyclic
  • STING1 protein, human
  • Sting1 protein, mouse
  • cyclic guanosine monophosphate-adenosine monophosphate