A Developed STING Agonist Has Systemic Antitumor Activity

Tumor-derived DNA activates the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway to enhance adaptive antitumor immunity. DNA activates cGAS to produce cGAMP, the ligand for the endoplasmic reticulum receptor STING. Downstream signaling results in increased production of IFN and other proinflammatory cytokines to promote cross-presentation of tumor antigens and mobilization of tumor-specific CD8 T cells. STING agonists are in clinical trials to treat patients with solid tumors. The available STING agonists are modified cyclic nucleotides that are delivered intratumorally and have achieved durable regressions in tumor models. However, STING agonists that can be delivered systemically in patients with cancer have not been developed, prompting Ramanjulu, Pesiridis, Yang, and colleagues to perform a high-throughput screen to identify ligands that compete with cGAMP for STING binding to modulate STING activity. This approach discovered two amidobenzimidazole (ABZI) compounds that inhibited cGAMP binding to STING. Crystal structures of each compound in complex with the STING C-terminal domain revealed binding to the cGAMP binding pocket, with two bound molecules per STING dimer. Based on these findings a linker was added between the two compounds to create a linked dimeric ABZI (diABZI), which exhibited enhanced binding to STING. Further optimization yielded compound 3, a more potent diABZI. Compound 3 functioned as a STING agonist, selectively activating STING. In vivo, compound 3 triggered a STING-dependent activation of type I IFN and proinflammatory cytokines. Further, intravenous injection of compound 3 induced durable tumor regression in a mouse model of colorectal cancer. Depletion of CD8⁺ T cells suppressed the antitumor activity, suggesting that compound 3 suppresses tumor growth by activating the adaptive immune response. The development of a non-nucleotide STING agonist that can be administered intravenously may expand the use of STING agonists in patients with cancer.

Ramanjulu JM, Pesiridis GS, Yang J, Concha N, Singhaus R, Zhang SY, et al. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature 2018 Nov 7 [Epub ahead of print].

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