2’3’-c-di-AM(PS)2 (Rp,Rp)

2’3’-c-di-AM(PS)2 (Rp,Rp) (ADU-S100), an activator of stimulator of interferon genes (STING), leads to potent and systemic tumor regression and immunity^[1]. IC50 & Target:STING^[1] In Vitro: 2’3’-c-di-AM(PS)2 (Rp,Rp) is unstable in its free base form. 2’3’-c-di-AM(PS)2 (Rp,Rp) ammonium salt (HY-12885B) improves both stability and lipophilicity, promoting significantly increased STING signaling as compared to endogenous and pathogen-derived cyclic dinucleotides (CDNs)^[1].
2’3’-c-di-AM(PS)2 (Rp,Rp) shows enhanced type I IFN production over CDA in THP-1 human monocytes. In contrast, the dithio, mixed-linkage CDN derivatives (ML RR-CDA, ML RR-S2 CDG, and ML RR-S2 cGAMP) potently activate all five hSTING alleles, including the refractory hSTING^REF and hSTING^Q alleles. 2’3’-c-di-AM(PS)2 (Rp,Rp) induces the highest expression of IFN-β and the pro-inflammatory cytokines TNF-α, IL-6, and MCP-1 on a molar equivalent basis, as compared to endogenous ML cGAMP and the TLR3 agonist poly I:C. 2’3’-c-di-AM(PS)2 (Rp,Rp) is also found to induce aggregation of STING and induce phosphorylation of TBK1 and IRF3 in mouse bone marrow macrophage (BMM). 2’3’-c-di-AM(PS)2 (Rp,Rp) induces significantly higher levels of IFN-α when compared to ML cGAMP^[1]. In Vivo: 2’3’-c-di-AM(PS)2 (Rp,Rp) shows higher anti-tumor control than the endogenous ML cGAMP. A dose response of the 2’3’-c-di-AM(PS)2 (Rp,Rp) compound is performed in B16 tumor-bearing mice, which identifies an optimal antitumor dose level that also elicites maximum tumor antigen-specific CD8⁺ T cell responses, and improves long-term survival to 50%^[1].