5′-Phosphorothioester Linked Cyclic Dinucleotides, Endo-S-CDNs, Displaying Impressive Antitumor Activities In Vivo when Dosed Subcutaneously

Cyclic dinucleotides (CDNs) have become popular as immunotherapies triggering an immune response achieved via their activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Many analogs of 2'3'-cGAMP, c-di-GMP, and c-di-AMP have been developed and shown as effective cancer vaccines and immuno-stimulators for the induction of both the adaptive and innate immune systems. Unfortunately, these CDNs have been dosed via intratumor route, which is not convenient, especially for tumors that are difficult to reach. We recently introduced endo-S-CDNs as potent STING agonists but in our prior report we did not evaluate the in vivo efficacies of these novel STING agonists. Herein, we conduct a more extensive structure activity relationship study as well as in vivo evaluation of our best endo-S-CDNs. We demonstrate that endo-S-CDNs can be dosed via subcutaneous route to provide robust protection against MC38 and B16-F10 tumor models.