High-yield interferon induction by 10-carboxymethyl-9-acridanone in mice and hamsters

Taylor, Jerry; Schoenherr, Christine; Grossberg, Sidney E.

doi:10.1128/aac.18.1.20

Cited by 40 publications

(19 citation statements)

References 10 publications

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“…DMXAA (5,6-dimethylxanthenone-4-acetic acid) is a potent chemical compound which can shrink solid tumors in mice by disrupting tumor vasculature and boosting the immune system by producing cytokines (18–20). CMA (10-carboxymethyl-9-acridanone) is an anti-viral compound that can induce type I interferons (21,22). Both DMXAA and CMA were recently co-crystallized with STING (9,23,24).…”

Section: Introductionmentioning

confidence: 99%

Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells

et al. 2016

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Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, interferon production and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Eμ-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3′3′-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3′3′-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost anti-tumoral immune responses, STING agonists can also directly eradicate malignant B cells.

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Section: Introductionmentioning

confidence: 99%

Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells

et al. 2016

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“…However, while most of these small‐molecule compounds showed excellent type I IFN induction and antiviral activities in rodents (Kramer et al , 1976; Taylor et al , 1980a, 1980b), these promising results failed to translate into the human system. Tilorone, for example, showed no type I IFN induction in the human system, both upon systemic or topic administration (Kaufman et al , 1971), and at the same time, research on CMA was abandoned by most groups.…”

Section: Introductionmentioning

confidence: 99%

Species-specific detection of the antiviral small-molecule compound CMA by STING

Cavlar

Deimling

Ablasser

et al. 2013

EMBO J

170

154

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Extensive research on antiviral small molecules starting in the early 1970s has led to the identification of 10-carboxymethyl-9-acridanone (CMA) as a potent type I interferon (IFN) inducer. Up to date, the mode of action of this antiviral molecule has remained elusive. Here we demonstrate that CMA mediates a cell-intrinsic type I IFN response, depending on the ER-resident protein STING. CMA directly binds to STING and triggers a strong antiviral response through the TBK1/IRF3 route. Interestingly, while CMA displays extraordinary activity in phosphorylating IRF3 in the murine system, CMA fails to activate human cells that are otherwise responsive to STING ligands. This failure to activate human STING can be ascribed to its inability to bind to the C-terminal ligandbinding domain of human STING. Crystallographic studies show that two CMA molecules bind to the central Cyclic diguanylate (c-diGMP)-binding pocket of the STING dimer and fold the lid region in a fashion similar, but partially distinct, to c-diGMP. Altogether, these results provide novel insight into ligand-sensing properties of STING and, furthermore, unravel unexpected species-specific differences of this innate sensor.

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“…Structural studies have shown that CDN binding is associated with an open-to-closed conformational change at STING CTD region corresponding to open-inactivated and close-activated states 6 17 18 19 . Chemical agents DMXAA (5,6-Dimethylxanthenone 4-acetic acid) and CMA (10-carboxymethyl-9-acridanone) have been screened and tested for excellent anticancer/antiviral effect earlier in mouse but failed in clinical trials 20 21 22 23 , and their effects have been identified lately to be via induction of type I IFN involved in STING-dependent immune responses 24 25 26 . Further studies revealed that DMXAA or CMA binds well to mouse STING (mSTING) rather than to human STING (hSTING) 18 27 .…”

mentioning

confidence: 99%

Rat and human STINGs profile similarly towards anticancer/antiviral compounds

Zhang

Han

Tao

et al. 2015

Sci Rep

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Cyclic dinucleotides (CDNs) and antitumor/antiviral agents (DMXAA and CMA) trigger STING-dependent innate immunity activation. Accumulative evidences have showed that DMXAA and CMA selectively activate mouse, but not human STING signaling. The mechanism underlying this species selectivity remains poorly understood. In this report, we have shown that human and rat STINGs display more similar signaling profiles toward DMXAA and CMA than that of human and mouse STINGs, suggesting that rat is more suitable for preclinical testing of STING-targeted drugs. We have also determined the crystal structures of both apo rat STING and its complex with cyclic GMP-AMP with 2′5′ and 3′5′ phosphodiester linkage (2′3′-cGAMP), a human endogenous CDN. Structure-guided biochemical analysis also revealed the functional importance of the connecting loop (A140-N152) between membrane and cytosolic domains in STING activation. Taken together, these findings reveal that rat STING is more closely related to human STING in terms of substrate preference, serving as a foundation for the development of STING-targeted drugs.

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High-yield interferon induction by 10-carboxymethyl-9-acridanone in mice and hamsters

Cited by 40 publications

References 10 publications

Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells

Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells

Species-specific detection of the antiviral small-molecule compound CMA by STING

Rat and human STINGs profile similarly towards anticancer/antiviral compounds

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