C92, a proton channel-blocking allosteric STING agonist generates robust antitumor activity.

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Stimulator of Interferon Genes (STING) activation is a key goal for cancer treatment.
• Orthosteric STING agonists have shown limited success in advanced cancers.
• C92 represents a novel class of allosteric STING agonists with unique binding and functional properties.

Purpose of the Study:

• To characterize the pharmacology of C92, a first-in-class allosteric STING agonist.
• To evaluate the anticancer efficacy of C92 in preclinical models.
• To explore the therapeutic potential of C92 as an immune therapeutic for cancer.

Main Methods:

• Radioligand binding assays to confirm allosteric binding.
• Studies in primary human and murine cells to assess Type I Interferon (IFN) immune signaling.
• Assessment of IFN-independent actions (inflammasome, autophagy) in THP-1 cells.
• In vivo evaluation of C92's anticancer activity in STING knock-in mice, alone and with checkpoint inhibitors (CPIs).

Main Results:

• C92 acts as an allosteric agonist, activating STING independently of cGAMP and potentiating cGAMP binding.
• The allosteric site is located within STING's proton channel.
• C92 induces strong Type I IFN responses without activating inflammasome or autophagy.
• C92 demonstrated robust antitumor immune responses and synergized with CPIs, supporting clinical translation.

Conclusions:

• C92, an allosteric small-molecule agonist, uniquely blocks STING's proton channel.
• Its distinct pharmacology differentiates C92 from orthosteric STING agonists.
• C92 is a promising immune therapeutic candidate for cancer treatment.