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 DNA 1. 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 adjuvants 2. 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 delivery 3. 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.
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Novel STING agonists such as diABZI and MSA-2 have been developed that could be systemically administered.
“Recently, some novel STING agonists such as diABZI and MSA-2 have been developed which could be systemically administrated [268, 269].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [268]
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- Authors
- Ramanjulu, J. M., Pesiridis, G. S., Yang, J., Concha, N., Singhaus, R., Zhang, S.-Y., Tran, J.-L., Moore, P., Lehmann, S., Eberl, H. C., Muelbaier, M., Schneck, J. L., Clemens, J., Adam, M., Mehlmann, J., Romano, J., Morales, A., Kang, J., Leister, L., Graybill, T. L., Charnley, A. K., Ye, G., Nevins, N., Behnia, K., Wolf, A. I., Kasparcova, V., Nurse, K., Wang, L., Puhl, A. C., Li, Y., Klein, M., Hopson, C. B., Guss, J., Bantscheff, M., Bergamini, G., Reilly, M. A., Lian, Y., Duffy, K. J., Adams, J., Foley, K. P., Gough, P. J., Marquis, R. W., Smothers, J., Hoos, A., & Bertin, J.
- Affiliations
- GlaxoSmithKline (United States) (US)
- GlaxoSmithKline (Germany) (DE)
- Corresponding author
- Ramanjulu, Joshi M.
- ORCID
- Ramanjulu, Joshi M.
- Pesiridis, G. Scott
- Yang, Jingsong
- Concha, Nestor
- Moore, Patrick
- Eberl, H. Christian
- Muelbaier, Marcel
- Charnley, Adam K.
- Nevins, Neysa
- Wolf, Amaya I.
- Wang, Liping
- Puhl, Ana C.
- Li, Yue
- Hopson, Christopher B.
- Bantscheff, Marcus
- Bergamini, Giovanna
- Lian, Yiqian
- Duffy, Kevin J.
- Foley, Kevin P.
- Gough, Peter J.
- Smothers, James
- Hoos, Axel
- Bertin, John
- Venue
- Nature
- Published
- 2018-11-07
- Volume
- 564
- Issue
- 7736
- Pages
- 439-443
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2900220188
- Cited by
- 912
- References
- 24
- Citations by year
- 2026: 133 · 2025: 157 · 2024: 148 · 2023: 125 · 2022: 108 · 2021: 104 · 2020: 82 · 2019: 52 · 2018: 2 · 2015: 1
- FWCI
- 26.30
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-05-30)
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- diABZI, cGAS-STING pathway, small molecule agonists, colon cancer, antitumor immunity, innate immune activation, intravenous administration, cancer immunotherapy
- MeSH terms
- STING Protein, Animals, Benzimidazoles, Colonic Neoplasms, Humans, Ligands, Membrane Proteins, Models, Molecular, Nucleotides, Cyclic, Drug Design, Mice
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