In recent years, immuno-oncology therapies have emerged as attractive alternatives and / or supplements to traditional methods of cancer treatment. While checkpoint inhibitors and other immune therapies have enjoyed clinical success and improved patient outcomes, even gaining approval as front line therapy in some cases, opportunities for further progress remain. One such strategy with the potential to provide synergy with existing immunotherapies is activation of the innate immune system. To that end, activation of the Stimulator of Interferon Genes (STING) pathway by endogenous or synthetic STING agonists results in a cascade response ultimately resulting in STING-dependent activation of innate immune response and enhanced anti-tumor efficacy in pre-clinical murine models. To identify STING agonists suitable for development as novel therapeutics, our group started with the endogenous ligand for STING, cyclic guanosine monophosphate–adenosine monophosphate (2’,3’-cGAMP) and embarked on a systematic investigation of SAR around modifications to that cyclic dinucleotide (CDN), including to the nucleobase, ribose, ribose substituents, phosphate linkers, and combinations thereof. A number of synthetic analogues from our group and others employ thiophosphates for both of the CDN linkages, which are well tolerated but their synthesis can produce up to four diastereomers owing to the chirality at the phosphorous center. This presentation will focus on exploration of combinations and permutations of phosphate, thiophosphate, and dithiophosphate linkages to reduce stereochemical complexity and streamline synthesis. We will report on the activity, stability, and <i>in vivo</i> efficacy of these novel STING agonists.

Effects of phosphate linker modifications on 2’,3’-cyclic dinucleotide STING agonists

2019 Spring National Meeting

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