Chin et al. identified a non-nucleotide, small-molecule STING agonist (SR-717) that activated STING by inducing a closed conformation similar to cGAMP. SR-717 induced IFNB1, CXCL10, and IL6 expression and phosphorylation of TBK1, IRF3, and p65 downstream of STING in THP1 cells in vitro. In a poorly immunogenic B16F10 murine melanoma model, SR-717 inhibited tumor growth, increased survival, and reduced lung metastasis in a STING-dependent manner. SR-717 increased activation of CD8+ T, natural killer, and dendritic cells and displayed better tumor control than, but did not synergize with, anti-PD-1 or anti-PD-L1 monotherapy.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. (2) California Institute for Biomedical Research, 11119 North T
Author Info: (1) Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. (2) California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA. (3) Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. (4) Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. (5) California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA. petrassi@scripps.edu jteijaro@scripps.edu llairson@scripps.edu. (6) Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. petrassi@scripps.edu jteijaro@scripps.edu llairson@scripps.edu. (7) Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. petrassi@scripps.edu jteijaro@scripps.edu llairson@scripps.edu.
#Contributed equally.
