Journal Article

Design of amidobenzimidazole STING receptor agonists with systemic activity

Schneck, Jessica L, Mehlmann, John, Concha, Nestor, Adam, Michael, Hopson, Christopher B, Ramanjulu, Joshi M, Eberl, H Christian, Marquis, Robert W, Bantscheff, Marcus, Kasparcova, Viera, Clemens, Jim, Lehmann, Stephanie, Puhl, Ana C, Leister, Lara, Guss, Jeffrey, Moore, Patrick, Adams, Jerry, Wolf, Amaya I, Foley, Kevin P, Charnley, Adam K, Yang, Jingsong, Muelbaier, Marcel, Romano, Joseph, Duffy, Kevin J, Tran, Jean-Luc, Graybill, Todd L, Smothers, James, Kang, James, Wang, Liping, Morales, Angel, Zhang, Shu-Yun, Klein, Michael, Hoos, Axel, Reilly, Michael A, Ye, Guosen, Bertin, John, Nevins, Neysa, Lian, Yiqian, Nurse, Kelvin, Gough, Peter J, Behnia, Kamelia, Bergamini, Giovanna, Pesiridis, G Scott, Li, Yue, Singhaus, Robert

2018

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Adjuvants / Agonists (Biochemistry) / Animals / Anticancer properties / Benzimidazoles - administration & dosage / Benzimidazoles - chemistry / Benzimidazoles - pharmacology / Benzimidazoles - therapeutic use / Cancer / Care and treatment / Clinical trials / Colon / Colon cancer / Colonic Neoplasms - drug therapy / Colonic Neoplasms - immunology / Dendritic cells / Deoxyribonucleic acid / Discovery and exploration / DNA / Drug Design / Endoplasmic reticulum / Genetic aspects / Humans / Hydrogen bonds / Immunologic research / Immunological research / Infectious diseases / Interferon / Intravenous administration / Kinases / Ligand binding (Biochemistry) / Ligands / Medical research / Medical treatment / Membrane Proteins - agonists / Membrane Proteins - immunology / Methods / Mice / Models, Molecular / Nucleotides, Cyclic - metabolism / Proteins / Stimulators / Synergism / Tumors