S-acylthioalkyl ester (SATE)-based prodrugs of deoxyribose cyclic dinucleotides (dCDNs) as the STING agonist for antitumor immunotherapy

Cancer immunotherapy is a powerful weapon in the fight against cancers. Cyclic dinucleotides (CDNs) have demonstrated the great potential by evoking the immune system to fight cancers. There are still a lot of unmet needs for highly active CDNs in clinical applications due to low cell permeation and serum stability. Here we reported S-acylthioalkyl ester (SATE)-based prodrugs of deoxyribose cyclic dinucleotides (dCDNs) with three different types of internucleotide linkages (3′,3′:11a; 2′,3′:11b; 2′,2′:11c). The parent dCDNs could be efficiently released from SATE-dCDNs by cellular esterases. Compared to 2′,3′-cGAMP and ADU-S100, 11a exhibited much higher potency of activating STING pathway and higher serum stability. In a CT26-Luc tumor-bearing animal model, 11a showed the efficient antitumor activity in eliminating the established tumor and induced significant increase of mRNA expression of IFN-β and other related inflammatory cytokines. Hence, SATE-dCDN prodrugs demonstrated their benefits in promoting cell penetration, improving serum stability, and thus enhancing bioactivity, suggesting their potential application as immunotherapy in a variety of malignancies. [Display omitted] •Three SATE-dCDN prodrugs (11a, 11b, and 11c) were designed as STING agonists.•11a was identified as a highly potent STING agonist with an EC50 value of 5.2 nM.•11a could suppress tumor growth in the CT26-Luc tumor-bearing mouse model.•11a and 11b led to significant cytokine induction.