Activation of the Stimulator of Interferon Genes (STING) pathway is a central innate immune sensing mechanism that leads to production of type I interferons and pro-inflammatory cytokines, maturation of antigen-presenting cells and priming of tumor antigen-specific CD8+ T-cells. Stimulation of this pathway in a tumor microenvironment therefore holds promise for generating an anti-tumor immune response. Accordingly, in various syngeneic mouse tumor models, STING agonists demonstrate robust tumor and plasma cytokine upregulation and strong anti-tumor activity, alone or in combination with anti-PD-1 monoclonal antibodies. Intratumoral injection of STING agonists thus represents a promising cancer treatment approach that is currently under investigation in human clinical trials in combination with recently approved checkpoint inhibitors.<br/>This talk will review synthetic chemistry approaches at Merck that enabled rapid exploration of the structurally and stereochemically complex cyclic dinucleotide (CDN) class of STING agonists. A variety of potent STING agonists were identified, many of which demonstrated greater than 100-fold improvements in efficacious dose in vivo when compared to the endogenous human CDN STING ligand, 2’,3’-cGAMP. Details in synthetic preparations of the diverse CDN STING agonists and their precursors, as well as structure activity relationships of these STING agonists will be discussed.

Discovery of novel cyclic dinucleotide STING agonists for cancer treatment

2019 Spring National Meeting

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