STING (Stimulator of Interferon Genes) is a master regulator of type I interferons and a key mediator of innate immunity. Activation of STING provides two critical anti-tumor responses – (1) The “spark” for initiating a robust innate immune response and (2) Priming and activation of a potent T cell mediated anti-tumor adaptive response. By serving as a bridge between the two arms of the immune system, activation of STING has the potential to transform the tumor microenvironment from immunologically “cold” to “hot” (inflamed), making otherwise resistant tumors respond to checkpoint blockade as well as other T cell targeting immunotherapies. Many preclinical and clinical drug discovery programs targeting STING activation are based on modifications of the naturally occurring cyclic dinucleotide (CDN) agonists. However, the CDN molecules suffer from poor drug-like properties and consequently cannot be delivered systemically. Thus, the benefits of STING activation by these first generation CDNs will be limited to only a subset of tumors that are accessible to intratumoral injection. The large, polar and charged binding site as well as the mechanism of activation of STING present unique drug discovery challenges to designing a small molecule that can induce the optimal, active conformation of the STING dimer while maintaining the physical-chemical properties required for systemic exposure. Using our proprietary physics-driven discovery engine with our integrative chemistry/biophysics/biology approach we have developed novel small molecule agonists of STING that exhibit selective and potent activity across all known isoforms of the human protein. Our small molecule agonist rapidly activates the STING/TBK1/IRF3 pathway (phosphorylation and translocation) and induces the expression of type I IFN in cells in a STING-dependent manner. Treatment of primary immune cells from healthy human donors results in the activation of dendritic cells and upregulation of costimulatory markers. Drug characteristics and STING pharmacology allow for unique dosing paradigm in vivo with robust induction of type I IFN after intravenous (i.v.) administration. A single i.v. dose produces potent and durable anti-tumor immunity and complete tumor regression in mice bearing syngeneic tumors. Activation of tumor directed T cell response provides long term protection against tumor re-challenge and effective systemic immunity. Our work highlights the tremendous potential of a small molecule STING agonist as a well-tolerated, systemically delivered cancer immunotherapeutic.

Citation Format: Meghana M Kulkarni, Timothy Dwight, Kristen Marino, Bryce K Allen, Mohammed Taimi, Cecilia Bastos, Sujen Lai, Cheryl Koh, Ramya Samant, Bethany Tesar, Huang Huang, Brian Chamberlain, James M Rice, Dazhi Tan, Zhixiong Lin, Sharon Shechter, Stella Li, Sam Sparks, Holly Soutter, Steven Swann, Woody Sherman, Christopher Winter. True small molecule STING agonist generates systemic and potent anti-tumor immunity required for effective cancer immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A20. doi:10.1158/1535-7163.TARG-19-LB-A20