Stimulator of Interferon Genes (STING) is an intracellular transmembrane receptor anchored to the endoplasmic reticulum and is a critical component for sensing cytosolic DNA. Recent studies have revealed STING’s role in mobilizing an innate immune response. Activation of the STING pathway induces production of type I interferons through interferon regulatory factor-3 (IRF-3) and leads to secretion of proinflammatory cytokines such as TNFα and IL-6 via the NF-kB pathway. Ultimately, in mouse models, STING activation can result in shrinkage of tumors and provide long lasting immunity. The natural ligand that binds to and activates STING is (2',3')cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). It is a cyclic dinucleotide (CDN) with a unique 2',3' linkage produced by cGAS in the presence of cytosolic double-stranded DNA from invading bacteria, viruses or protozoa or in the case of cancer self-DNA. Previous approaches to mimic cGAMP embarked on modifications of CDN’s, including changes to the nucleobase, ribose, ribose substituents, phosphate linkers, and various combinations of them. Our approach towards STING agonists suitable for development focused on redesign of the macrocylic portion of CDNs while maintaining the spatial arrangement of the key interactions of CDN’s with STING. We hypothesized that the ribose of CDN’s acted as elaborate linkage holding key features in place needed to bind to and activate STING. The aforementioned key features, nucleobases as well as phosphodiesters, can be arranged in a CDN mimicking fashion by choosing different attachment points to nucleobases thus eliminating the necessity to include a sugar moiety. To incorporate conformational variation in the design of the key features a modular approach was chosen. Successful implementation of this strategy led to the identification of novel STING agonists that demonstrated improved in vivo activity.

Design, synthesis, and optimization of a novel class of macrocyclic STING agonists

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.