PROJECT SUMMARY Cellular innate immune sensors, such as STING (STIMULATOR OF INTERFERON GENES), have evolved to detect microbial infection of the cell (1-3). STING controls the potent cytosolic DNA-stimulated innate immune pathways and is activated by cyclic dinucleotides (CDNs) such as cyclic di-GMP and cyclic-di-AMP secreted by intracellular bacteria following infection. Alternatively, STING can be activated by cyclic GMP-AMP (cGAMP) generated by a cellular cGAMP synthase cGAS (MB21D1) after association with aberrant cytosolic dsDNA species, which can include microbial DNA or self-DNA leaked from the nucleus (4). Association with CDNs enables STING to activate the production of type I interferon (IFN) and pro-inflammatory cytokines, which facilitate adaptive immunity (3). Aside from being critical for the protection against microbial infection, STING signaling has been shown to be essential for facilitating robust anti-tumor immunity. Regulation of the immune system to stimulate anti-tumor cytotoxic T cell responses is proving to be a powerful approach for the effective treatment of a variety of cancers. For example, STING agonists, based on synthetic CDNs, have been shown to exert potent anti-tumor properties likely by stimulating APCs and are now being evaluated in Phase I trials for the treatment of cancer. However, such CDNs are highly labile and do not exert potent activity when given systemically. This has limited their use/evaluation to intratumoral and oral administration. Here, we describe a new generation of novel small STING agonists that activate STING signaling, that appear superior to existing CDN’s, for evaluation in anti-tumor therapeutic strategies. The compounds have been generated by STINGINN LLC, based in Miami, in collaboration with the University of Miami School of Medicine, FL.

PROJECT NARRATIVE Stimulation of the immune system has been shown to be a powerful approach for the treatment of cancer. We have found that stimulation of an immune pathway controlled by a cellular molecule referred to as STING can effectively trigger anti-tumor responses. Here, we have generated a new array of STING-dependent compounds that we intend to evaluate as anti-cancer drugs.