2. Academic Validation
  3. Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

  • J Med Chem. 2022 Oct 27;65(20):14082-14103. doi: 10.1021/acs.jmedchem.2c01305.
Zdeněk Vavřina 1 2,  Pavla Perlíková 1 3,  Nemanja Milisavljević 1 4,  Florian Chevrier 1,  Miroslav Smola 1,  Joshua Smith 1 5,  Milan Dejmek 1,  Vojtěch Havlíček 1 4,  Miloš Buděšínský 1,  Radek Liboska 1,  Lenka Vaneková 1 6,  Jiří Brynda 1,  Evzen Boura 1,  Pavlína Řezáčová 1,  Michal Hocek 1,  Gabriel Birkuš 1
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo Namesti 542, Prague 166 10, Czech Republic.
  • 2 Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030/8, Prague 128 00, Czech Republic.
  • 3 Department of Organic Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology, Technicka 5, Prague 166 28, Czech Republic.
  • 4 Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 2030/8, Prague 128 00, Czech Republic.
  • 5 First Faculty of Medicine, Charles University, Katerinska 1660/32, Prague 121 08, Czech Republic.
  • 6 Department of Cell Biology, Faculty of Science, Charles University, Vinicna 1594/7, Prague 128 43, Czech Republic.
PMID: 36201304 DOI: 10.1021/acs.jmedchem.2c01305
Abstract

Cyclic dinucleotides (CDNs) are second messengers that activate stimulator of interferon genes (STING). The cGAS-STING pathway plays a promising role in Cancer Immunotherapy. Here, we describe the synthesis of CDNs containing 7-substituted 7-deazapurine moiety. We used mouse Cyclic GMP-AMP Synthase and Bacterial dinucleotide synthases for the enzymatic synthesis of CDNs. Alternatively, 7-(het)aryl 7-deazapurine CDNs were prepared by Suzuki-Miyaura cross-couplings. New CDNs were tested in biochemical and cell-based assays for their affinity to human STING. Eight CDNs showed better activity than 2'3'-cGAMP, the natural ligand of STING. The effect on cytokine and chemokine induction was also evaluated. The best activities were observed for CDNs bearing large aromatic substituents that point above the CDN molecule. We solved four X-ray structures of complexes of new CDNs with human STING. We observed π-π stacking interactions between the aromatic substituents and Tyr240 that are involved in the stabilization of CDN-STING complexes.

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