Cellular innate immune sensors, such as STING (STIMULATOR OF INTERFERON GENES), have evolved todetect microbial infection of the cell (1-3). STING controls the potent cytosolic DNA-stimulated innate immunepathways and is activated by cyclic dinucleotides (CDNs) such as cyclic di-GMP and cyclic-di-AMP secreted byintracellular 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 dsDNAspecies, which can include microbial DNA or self-DNA leaked from the nucleus (4). Association with CDNsenables STING to activate the production of type I interferon (IFN) and pro-inflammatory cytokines, whichfacilitate adaptive immunity (3). Aside from being critical for the protection against microbial infection, STINGsignaling has been shown to be essential for facilitating robust anti-tumor immunity. Regulation of theimmune system to stimulate anti-tumor cytotoxic T cell responses is proving to be a powerful approach for theeffective treatment of a variety of cancers. For example, STING agonists, based on synthetic CDNs, have beenshown to exert potent anti-tumor properties likely by stimulating APCs and are now being evaluated in Phase Itrials for the treatment of cancer. However, such CDNs are highly labile and do not exert potent activity whengiven systemically. This has limited their use/evaluation to intratumoral and oral administration. Here, wedescribe a new generation of novel small STING agonists that activate STING signaling, that appear superior toexisting CDN's, for evaluation in anti-tumor therapeutic strategies. The compounds have been generated bySTINGINN LLC, based in Miami, in collaboration with the University of Miami School of Medicine, FL.
Public Health Relevance Statement: 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.
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