Cyclic dinucleotide (CDN) agonists of the adaptor protein STING (Stimulator of Interferon Genes) have recently attracted intense interest due to their structural complexity and their dramatic anti-tumor effects in preclinical mouse models. Similar to the endogenous STING ligand 2’3’-cGAMP, the isomeric CDN 2’2’-cGAMP has been reported to bind STING and induce conformational changes that lead to production of type-I interferons and pro-inflammatory cytokines. Herein we present the team’s efforts in design, synthesis and optimization of novel 2’2’-CDNs as a promising class of STING agonists. We demonstrate that, similar to 2’3’-CDNs, intratumoral delivery of a prototype 2’2’-cGAMP analog effects complete tumor regression in a syngeneic mouse tumor model. To enable broad SAR exploration in this series, we sought alternatives to the well-documented, lengthy total syntheses required to prepare CDNs. Employing high throughput experimentation (HTE) techniques, we have discovered and developed novel cyclo-dimerization processes to streamline the synthesis of 2’2’-CDNs, leading to a significantly accelerated design-synthesis-test cycle . Employing molecular modeling and X-ray crystallography, we have elucidated similarities and differences in the binding of 2’2’- and 2’,3’-CDNs to STING. Structure based drug design (SBDD) in combination with our improved cyclo-dimerization chemistry further accelerated discovery of structurally differentiated 2’2’-CDNs with favorable in vitro and in vivo activities.

Design, synthesis, and optimization of 2’2’-cyclic dinucleotides as STING agonists

2019 Spring National Meeting

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