PDE-stable 2'3'-cGAMP analogues, containing 5'-S-phosphorothioester linkage, as STING agonists.

The stimulator of interferon genes (STING) has emerged as a promising target for cancer immunotherapy. 2'3'-cGAMP, a natural agonist of STING, shows anticancer activity stimulation of immune cells but it is susceptible to degradation by hydrolytic enzymes. Consequently, the cyclic dinucleotide analogues that are being evaluated in the clinic as immunotherapies contain the hydrolytically stable phosphorothioate moiety, whereby the sulfur moiety is exo to the phosphate containing ring.

2',4'-LNA-Functionalized 5'-S-Phosphorothioester CDNs as STING Agonists.

Cyclic dinucleotides (CDNs) have garnered popularity over the last decade as immunotherapeutic agents, which activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to trigger an immune response. Many analogs of 2'3'-cGAMP, c-di-GMP, and c-di-AMP have been developed and shown as effective cancer vaccines and immunomodulators for the induction of both the adaptive and innate immune systems. Unfortunately, the effectiveness of these CDNs is limited by their chemical and enzymatic instability.