6DXG

amidobenzimidazole (ABZI) STING agonists

Summary for 6DXG

• Entry DOI: 10.2210/pdb6dxg/pdb
• Descriptor: Stimulator of interferon protein, CALCIUM ION, 2-[(1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)amino]-1-[(2R)-2-hydroxy-2-phenylethyl]-1H-benzimidazole-5-carboxamide, ... (4 entities in total)
• Functional Keywords: agonist, sting (stimulator of interferon genes), transmembrane protein 173 (tmem173), immune system, immune system-inhibitor complex, immune system-agonist complex, immune system/agonist
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 22390.19

Authors

Concha, N.O. (deposition date: 2018-06-28, release date: 2018-11-07, Last modification date: 2023-10-11)

Primary citation

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.,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.
Design of amidobenzimidazole STING receptor agonists with systemic activity.
Nature, 564:439-443, 2018

PubMed 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. 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. 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. 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.

PubMed: 30405246
DOI: 10.1038/s41586-018-0705-y

Experimental method

X-RAY DIFFRACTION (1.905 Å)