STING Agonist

STING Protein Animation

STimulator of Interferon Genes (STING) 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.
  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 and other T cell-directed immunotherapies.

First generation STING agonists are structural mimetics of endogenous agonists, cyclic dinucleotides (CDNs) and do not have the requisite drug-like properties (poor physiochemical properties and metabolically unstable). Consequently, they cannot be delivered systemically and are limited in use to local delivery via intra-tumoral injection.

To address these limitations, the Silicon Therapeutics team has developed the novel small molecule STING agonist (SNX281) with excellent drug properties permitting systemic delivery. SNX281 is potent, specific, and active against all human isoforms of STING and rapidly activates downstream signaling and induces type I IFN. Treatment of primary immune cells from human donors results in the activation of dendritic cells and upregulation of co-stimulatory markers. In vivo, SNX281 simulates cross-presentation, antigen-specific T cell response, and a rapid multi-lineage anti-tumor immunity.

SNX281 drug characteristics and STING pharmacology allow for a unique dosing paradigm with robust induction of type I IFN after a short duration of exposure. A single I.V. dose produces potent and durable anti-tumor immunity and complete tumor regression in mice. Activation of tumor-directed T cell response provides long-term protection against tumor re-challenge and effective systemic immunity.

References

X. Zhang et al., Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51, 226–235 (2013). doi: 10.1016/j.molcel.2013.05.022; pmid: 23747010

L. Corrales et al., Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep. 11, 1018–1030 (2015). doi: 10.1016/j.celrep.2015.04.031; pmid: 25959818

G. Berger, M. Marloye, S. E. Lawler, Pharmacological Modulation of the STING Pathway for Cancer Immunotherapy. Trends Mol. Med. 25, 412–427 (2019). doi: 10.1016/j.molmed.2019.02.007; pmid: 30885429