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

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

Emily N Chin  1 , Chenguang Yu #  1   2 , Vincent F Vartabedian #  3 , Ying Jia #  1   3 , Manoj Kumar  2 , Ana M Gamo  2 , William Vernier  2 , Sabrina H Ali  1 , Mildred Kissai  1 , Daniel C Lazar  3 , Nhan Nguyen  3 , Laura E Pereira  1 , Brent Benish  2 , Ashley K Woods  2 , Sean B Joseph  2 , Alan Chu  2 , Kristen A Johnson  2 , Philipp N Sander  1 , Francisco Martínez-Peña  1 , Eric N Hampton  2 , Travis S Young  2 , Dennis W Wolan  4 , Arnab K Chatterjee  2 , Peter G Schultz  1   2 , H Michael Petrassi #  5 , John R Teijaro  6 , Luke L Lairson  7
Affiliations

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

Emily N Chin et al. Science. .

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.

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Comment in

  • Immunotherapy with a sting.
    Gajewski TF, Higgs EF. Gajewski TF, et al. Science. 2020 Aug 21;369(6506):921-922. doi: 10.1126/science.abc6622. Science. 2020. PMID: 32820113 No abstract available.
  • Strengthening the sting of immunotherapy.
    Crunkhorn S. Crunkhorn S. Nat Rev Drug Discov. 2020 Oct;19(10):669. doi: 10.1038/d41573-020-00148-3. Nat Rev Drug Discov. 2020. PMID: 32843723 No abstract available.
  • Strengthening the sting of immunotherapy.
    Crunkhorn S. Crunkhorn S. Nat Rev Immunol. 2020 Oct;20(10):589. doi: 10.1038/s41577-020-00447-1. Nat Rev Immunol. 2020. PMID: 32901152 No abstract available.

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