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

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.