Synthesis and structure-activity evaluation of a series of novel tricyclic STING activators

A novel small molecule tricyclic series of STING activators was designed, synthesized and evaluated for human STING activity. These STING agonists were optimized from an initial set of structures with low potency through iterative cycles of design, synthesis and biological evaluation to yield compounds with potent human STING activity. The binding and functional properties of 68, an exemplar from the series were determined. Further, while 68 activated major variants of human STING it did not activate murine STING. Treatment of human PBMCs led to pathway engagement and the release of pro-inflammatory cytokines. When administered intra-tumorally, 68 caused robust retardation in the growth of MCA205 mouse fibrosarcoma tumors in human STING knock-in mice.