G10 is a direct activator of human STING

Banerjee, Monali; Middya, Sandip; Shrivastava, Ritesh; Basu, Sourav; Ghosh, Rajib; Pryde, David C.; Yadav, Dharmendra B.; Surya, Arjun

doi:10.1371/journal.pone.0237743

Cited by 21 publications

(15 citation statements)

References 27 publications

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“…G10 was shown to selectively activate INF/IRF3 signaling. While it was postulated that the agonistic effects may not be due to the direct activation of STING by G10, in vitro experiments utilizing the stimulation of HEK293T harboring a luciferase reporter expressed with an ISRE/ISG promoter using G10 confirmed G10 to be a weak direct binder of STING, with differing potencies to the STING variant expressed [79].…”

Section: Discussionmentioning

confidence: 99%

Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

et al. 2021

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Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

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Section: Discussionmentioning

confidence: 99%

Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

et al. 2021

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“…Scientists at Curadev Pharma discovered that certain bicyclic benzamides could target the STING pathway as the compounds demonstrated the ability to induce the production of STING-associated cytokines ( e.g. , type I IFNs, CXCL10, and TNF-α). − Notably, a set of three intratumoral injections of their lead compounds administered every other day led to significant suppression of tumor growth in BALB/c mice with hSTING-expressing CT26 tumors. Investigators at Merck explored benzothiophene derivatives in the context of STING activation and identified compounds with micromolar potency in both direct STING binding and a cellular reporter assay for type I IFN production .…”

Section: Sting Pathway Agonistsmentioning

confidence: 99%

Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy

2022

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The stimulator of interferon genes (STING) cellular signaling pathway is a promising target for cancer immunotherapy. Activation of the intracellular STING protein triggers the production of a multifaceted array of immunostimulatory molecules, which, in the proper context, can drive dendritic cell maturation, antitumor macrophage polarization, T cell priming and activation, natural killer cell activation, vascular reprogramming, and/or cancer cell death, resulting in immune-mediated tumor elimination and generation of antitumor immune memory. Accordingly, there is a significant amount of ongoing preclinical and clinical research toward further understanding the role of the STING pathway in cancer immune surveillance as well as the development of modulators of the pathway as a strategy to stimulate antitumor immunity. Yet, the efficacy of STING pathway agonists is limited by many drug delivery and pharmacological challenges. Depending on the class of STING agonist and the desired administration route, these may include poor drug stability, immunocellular toxicity, immune-related adverse events, limited tumor or lymph node targeting and/or retention, low cellular uptake and intracellular delivery, and a complex dependence on the magnitude and kinetics of STING signaling. This review provides a concise summary of the STING pathway, highlighting recent biological developments, immunological consequences, and implications for drug delivery. This review also offers a critical analysis of an expanding arsenal of chemical strategies that are being employed to enhance the efficacy, safety, and/or clinical utility of STING pathway agonists and lastly draws attention to several opportunities for therapeutic advancements.

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“…[31] Unlike CDN-mimetic STING agonists, G10, a human STING agonist, agonized STING-IRF3 cascade by directly interacting with human STING protein. [32] Although this report did not include STING-mediated cancer immunotherapy, G10 might be utilized for cancer immunotherapy in clinical models as G10 has strong affinity with human STING protein and can initiate STING activation. [32] Up to this point, all the STING agonists discussed have been administered intratumorally, to improve in their clinical translation, recent studies have aimed at systemically administrable STING agonists.…”

Section: Sting-binding Moleculesmentioning

confidence: 99%

Harnessing cGAS‐STING Pathway for Cancer Immunotherapy: From Bench to Clinic

Lee

Huntoon

Kang

et al. 2022

Advanced Therapeutics

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Recent advances in cancer immunotherapy have accomplished clinical successes in certain cancer models over the past decade. However, cancer treatments with adoptive cell transfer or immune checkpoint blockade (ICB) have shown critical limitations against solid tumors, which comprise the majority of human cancers. Thus, novel cancer immunotherapy which harnesses innate immunity process may be required in these tumor types. Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, one of the innate immune sensors, has gained interest in the field of immuno-oncology as activation of this pathway can drive both innate and adaptive immune responses among immunosuppressive tumor microenvironments. Recently, various cGAS-STING-activating strategies have been intensively investigated to achieve durable and widespread therapeutic responses in in vivo models. These meaningful preclinical outcomes have enabled several clinical trials. This review discusses agents targeting various aspects of the cGAS-STING pathway in cancer immunotherapy from benchtop to bedside. Moreover, various approaches to improve the clinical feasibility of cGAS-STING-activating strategies are delineated.

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G10 is a direct activator of human STING

Cited by 21 publications

References 27 publications

Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy

Harnessing cGAS‐STING Pathway for Cancer Immunotherapy: From Bench to Clinic

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