研究领域

Design of amidobenzimidazole STING receptor agonists with systemic activity

发布时间:2018/11/18 浏览量:108

Joshi M. ramanjulu1,5*, G. Scott Pesiridis1,5, Jingsong Yang2,5, Nestor Concha4, robert Singhaus1, Shu-Yun Zhang2, Jean-Luc tran1, Patrick Moore1, Stephanie Lehmann3, H. Christian eberl3, Marcel Muelbaier3, Jessica L. Schneck4, Jim Clemens4, Michael Adam2, John Mehlmann1, Joseph romano1, Angel Morales1, James Kang1, Lara Leister1, todd L. Graybill1, Adam K. Charnley1, Guosen Ye4, Neysa Nevins4, Kamelia Behnia1, Amaya I. Wolf1, Viera Kasparcova1, Kelvin Nurse4, Liping Wang4, Yue Li4, Michael Klein4, Christopher B. Hopson2, Jeffrey Guss4, Marcus Bantscheff3, Giovanna Bergamini3,Michael A. reilly1, Yiqian Lian2, Kevin J. Duffy2, Jerry Adams2, Kevin P. Foley1, Peter J. Gough1, robert W. Marquis1,James Smothers2,6, Axel Hoos2,6 & John Bertin1,6

Nature 2018 Nov 07   DOI: 10.1038/s41586-018-0705-y

 

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 immunemodifying cancer therapies.

全文链接:https://www.nature.com/articles/s41586-018-0705-y/tables/

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