6dxg | pdb_00006dxg
amidobenzimidazole (ABZI) STING agonists
Structural highlights
Publication Abstract from PubMedStimulator 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. Design of amidobenzimidazole STING receptor agonists with systemic activity.,Ramanjulu JM, Pesiridis GS, Yang J, Concha N, Singhaus R, Zhang SY, Tran JL, Moore P, Lehmann S, Eberl HC, Muelbaier M, Schneck JL, Clemens J, Adam M, Mehlmann J, Romano J, Morales A, Kang J, Leister L, Graybill TL, Charnley AK, Ye G, Nevins N, Behnia K, Wolf AI, Kasparcova V, Nurse K, Wang L, Li Y, Klein M, Hopson CB, Guss J, Bantscheff M, Bergamini G, Reilly MA, Lian Y, Duffy KJ, Adams J, Foley KP, Gough PJ, Marquis RW, Smothers J, Hoos A, Bertin J Nature. 2018 Dec;564(7736):439-443. doi: 10.1038/s41586-018-0705-y. Epub 2018 Nov, 7. PMID:30405246[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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