Design of amidobenzimidazole STING receptor agonists with systemic activity.

Abstract

Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies.

• Authors: Joshi M Ramanjulu, G Scott Pesiridis, Jingsong Yang, Nestor Concha, Robert Singhaus, Shu-Yun Zhang, Jean-Luc Tran, Patrick Moore, Stephanie Lehmann, H Christian Eberl, Marcel Muelbaier, Jessica L Schneck, Jim Clemens, Michael Adam, John Mehlmann, Joseph Romano, Angel Morales, James Kang, Lara Leister, Todd L Graybill, Adam K Charnley, Guosen Ye, Neysa Nevins, Kamelia Behnia, Amaya I Wolf, Viera Kasparcova, Kelvin Nurse, Liping Wang, Ana C Puhl, Yue Li, Michael Klein, Christopher B Hopson, Jeffrey Guss, Marcus Bantscheff, Giovanna Bergamini, Michael A Reilly, Yiqian Lian, Kevin J Duffy, Jerry Adams, Kevin P Foley, Peter J Gough, Robert W Marquis, James Smothers, Axel Hoos, John Bertin
• Journal: Nature (Nature) Vol. 564 Issue 7736 Pg. 439-443 (12 2018) ISSN: 1476-4687 [Electronic] England
• PMID: 30405246 (Publication Type: Journal Article)

Chemical References

• Benzimidazoles
• Ligands
• Membrane Proteins
• Nucleotides, Cyclic
• STING1 protein, human
• Sting1 protein, mouse
• cyclic guanosine monophosphate-adenosine monophosphate

Topics

• Animals
• Benzimidazoles (administration & dosage, chemistry, pharmacology, therapeutic use)
• Colonic Neoplasms (drug therapy, immunology)
• Drug Design
• Humans
• Ligands
• Membrane Proteins (agonists, immunology)
• Mice
• Models, Molecular
• Nucleotides, Cyclic (metabolism)