2. Academic Validation
  3. Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy

Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy

  • Eur J Med Chem. 2023 Nov 5;259:115685. doi: 10.1016/j.ejmech.2023.115685.
Milan Dejmek 1,  Andrea Brazdova 2,  Tomáš Otava 3,  Marketa Pimkova Polidarova 2,  Martin Klíma 1,  Miroslav Smola 1,  Zdenek Vavrina 4,  Miloš Buděšínský 1,  Martin Dračínský 1,  Radek Liboska 1,  Evzen Boura 1,  Gabriel Birkuš 5,  Radim Nencka 6
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, Prague 6, 166 10, Czech Republic.
  • 2 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, Prague 6, 166 10, Czech Republic; Department of Genetics and Microbiology, Faculty of Science, Charles University, Průmyslová 595, Vestec, 128 44, Prague, Czech Republic.
  • 3 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, Prague 6, 166 10, Czech Republic; Faculty of Food and Biochemical Technology, University of Chemistry and Technology, 166 28, Prague 6, Czech Republic.
  • 4 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, Prague 6, 166 10, Czech Republic; Faculty of Science, Charles University, Albertov 6, Prague 2, 128 00, Czech Republic.
  • 5 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, Prague 6, 166 10, Czech Republic. Electronic address: [email protected].
  • 6 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, Prague 6, 166 10, Czech Republic. Electronic address: [email protected].
PMID: 37567057 DOI: 10.1016/j.ejmech.2023.115685
Abstract

Cyclic dinucleotides (CDNs) trigger the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which plays a key role in cytosolic DNA sensing and thus in immunomodulation against infections, cell damage and Cancer. However, Cancer Immunotherapy trials with CDNs have shown immune activation, but not complete tumor regression. Nevertheless, we designed a novel class of CDNs containing vinylphosphonate based on a STING-affinity screening assay. In vitro, acyloxymethyl phosphate/phosphonate prodrugs of these vinylphosphonate CDNs were up to 1000-fold more potent than the clinical candidate ADU-S100. In vivo, the lead prodrug induced tumor-specific T cell priming and facilitated tumor regression in the 4T1 syngeneic mouse model of breast Cancer. Moreover, we solved the crystal structure of this ligand bound to the STING protein. Therefore, our findings not only validate the therapeutic potential of vinylphosphonate CDNs but also open up opportunities for drug development in Cancer Immunotherapy bridging innate and adaptive immunity.

Keywords

Cancer; Cyclic dinucleotides; Immunotherapy; Intratumoral administration; STING.

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