title: Anticancer flavonoids are mouse-selective STING agonists.
abstract: The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor-specific vascular damage and other antitumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the antitumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy.
authors.affiliation: Department of Systems Biology, Harvard Medical School , Boston 02115, Massachusetts, United States.
authors.forename: Sujeong
authors.initials: S
authors.lastname: Kim
authors.forename: Lingyin
authors.initials: L
authors.lastname: Li
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Maliga
authors.forename: Qian
authors.initials: Q
authors.lastname: Yin
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mitchison
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008565:Membrane Proteins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000494:pharmacology; D000099197:STING Protein
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D008565:Membrane Proteins; D044004:Xanthones; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C066668:vadimezan