Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation

Xie, Zuoquan; Wang, Zhen; Fan, Fengying; Zhou, Jinpei; Hu, Zhaoxue; Wang, Qingxia; Wang, Xiyuan; Zeng, Qian; Zhang, Yan; Qiu, Jiaxuan; Zhou, Xinping; Xu, Hui; Bai, Hudagula; Zhan, Zhengsheng; Ding, Jian; Zhang, Huibin; Duan, Wenhu; Yu, Xuekui; Geng, Meiyu

doi:10.1038/s41421-022-00481-4

Cited by 22 publications

(29 citation statements)

References 56 publications

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“…In contrast, cytotoxic CD8T cells showed a delayed increase, observed at 72 h of treatment, which is concordant with the effects of known STING agonist like SR-717 20 and HB3089. 21 This suggests a sequential activation of the innate and adaptive immune responses against the tumor following treatment with C202. In contrast, we did not find significant changes in the proportion of DCs and CD4T cells within the CT26 tumor microenvironment after treatment with C202.…”

Section: Discussionmentioning

confidence: 99%

“…293T‐Dual hSTING‐H232 Cells, 293T‐Dual hSTING‐R232 Cells and 293T‐Dual hSTING‐AQ cells containing an ISG‐inducible secreted embryonic alkaline phosphatase (SEAP) reporter along with stable transfection of the H232 or R232 or AQ isoform of human STING (hSTING). ISG reporter was determined according to the previous method, 21 and the ISG‐fold change was calculated relative to the vehicle.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, engineered bacteria expressing CDNs have also been developed for anti‐tumor purposes 16,17 . Non‐CDN agonists have attracted increasing attention, such as diABZI, 18 MSA‐2, 19 SR‐717, 20 HB3089, 21 etc. diABZI, a class of dimeric STING agonists are suitable for intravenous administration, 18 and several studies have focused on structural modifications and SAR.…”

Section: Introductionmentioning

confidence: 99%

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A novel STING agonist with systemic and durable anti‐tumour activity

Wang,

Shen,

Zhang

et al. 2023

Clinical and Translational Dis

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BackgroundStimulator of interferon genes (STING) has emerged as a crucial and promising target in tumor immunotherapy in recent years. Its agonists play a vital role in activating both innate and adaptive immune responses to combat cancer. Currently, STING agonists are primarily administered through intratumoral or intravenous injection, with only a few could be administered by orally. Therefore, orally available STING agonists are urgently needed to be developed.Approach and resultsBased on previous structure‐activity relationship (SAR) studies, we made a structure modification to MSA‐2 by replacing the carbonyl group with a difluoromethylene to get a new compound 202 (C202) that exhibited better plasma exposure and oral bioavailability than MSA‐2. Thus, we conducted extensive pharmacological evaluations to understand its effects. C202 demonstrated the ability to activate various human STING isoforms and murine STING protein, showcasing a potent and specific activation of the STING signalling pathway at cellular level. In diverse immunocompetent mouse models representing both ‘cold’ and ‘hot’ tumors, C202, whether administered intratumorally or orally, displayed broad‐spectrum anti‐tumor activity. Encouragingly, it induced complete tumor regression in several tumor models of mice and stimulated immune memory effects, contributing to long‐term immune response against cancer. Additionally, our investigations into the impact of C202 on the tumor microenvironment found that it enhanced the anti‐tumor response of both innate and adaptive immune systems, bolstering the immune‐mediated fight against tumors. Furthermore, we made an intriguing observation regarding C202's synergistic effects. It was found to enhance the anti‐tumor activity of chemotherapy drug gemcitabine and the angiogenesis inhibitor AL3810, which provide potential combination therapies in future translational studies.ConclusionsOur research highlights C202 as a novel STING agonist with durable anti‐tumor activity that can be administered orally, presenting a promising candidate for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel STING agonist with systemic and durable anti‐tumour activity

Wang,

Shen,

Zhang

et al. 2023

Clinical and Translational Dis

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“…320,321 Among those being investigated extensively for preclinical characterization are summarized in Table 4, including bacterial vectors (such as SYNB1891 and STACT-TREX-1), ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) inhibitors, s-acylthioalkyl ester (SATE)-based STING-activation prodrugs selenium-containing chemicals based on the structure of benzothiophene oxobutanoic acid (MSA-2), newly developed 7-(het)aryl 7-deazapurine CDNs, small-molecule STING agonist include SR-001, SR-012, SR-717, SR-301 and SR-717, as well as novel compound named HB3089, and so on. [322][323][324][325][326] These preclinical small molecular STING agonists have been recently extensively reviewed by Garland et al, 327 and will therefore not be discussed in detail in this review.…”

Section: Targeting the Cgas-sting Signaling Pathway In Cancer Preclin...mentioning

confidence: 99%

Lipid‐based nanoparticles as drug delivery systems for cancer immunotherapy

Yang

Zhou

et al. 2023

MedComm

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Immune checkpoint inhibitors (ICIs) have shown remarkable success in cancer treatment. However, in cancer patients without sufficient antitumor immunity, numerous data indicate that blocking the negative signals elicited by immune checkpoints is ineffective. Drugs that stimulate immune activation‐related pathways are emerging as another route for improving immunotherapy. In addition, the development of nanotechnology presents a promising platform for tissue and cell type‐specific delivery and improved uptake of immunomodulatory agents, ultimately leading to enhanced cancer immunotherapy and reduced side effects. In this review, we summarize and discuss the latest developments in nanoparticles (NPs) for cancer immuno‐oncology therapy with a focus on lipid‐based NPs (lipid‐NPs), including the characteristics and advantages of various types. Using the agonists targeting stimulation of the interferon genes (STING) transmembrane protein as an exemplar, we review the potential of various lipid‐NPs to augment STING agonist therapy. Furthermore, we present recent findings and underlying mechanisms on how STING pathway activation fosters antitumor immunity and regulates the tumor microenvironment and provide a summary of the distinct STING agonists in preclinical studies and clinical trials. Ultimately, we conduct a critical assessment of the obstacles and future directions in the utilization of lipid‐NPs to enhance cancer immunotherapy.

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“…Research findings indicate that diverse monomolecular benzimidazole agonists can effectively inhibit the proliferation of various tumor cell lines, exhibiting potent antitumor activity. The series of derivatives have exhibited favorable pharmacological properties and show promising potential for clinical application, requiring further research on medicinal optimization [130a,132] . Among them, representative work is reported by Prof. Wang's team and Prof. You′s team (Figure 11).…”

Section: Sting Agonists For Cancer Therapymentioning

confidence: 99%

Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

Xuan,

2023

ChemMedChem

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Stimulator of interferon genes (STING) is a crucial adaptor protein in the innate immune response. STING activation triggers cytokine secretion, including type Ⅰ interferon and initiates T cell‐mediated adaptive immunity. The activated immune system converts "cold tumors" into "hot tumors" that are highly responsive to T cells by recruiting them to the tumor microenvironment, ultimately leading to potent and long‐lasting anti‐tumor effects. Unlike most immune checkpoint inhibitors, STING agonists represent a groundbreaking class of innate immune agonists that hold great potential for effectively targeting various cancer populations and are poised to become a blockbuster in tumor immunotherapy. This review will focus on the correlation between the STING signaling pathway and tumor immunity, as well as explore the impact of STING activation on other biological processes. Ultimately, we will summarize the development and optimization of STING agonists from a medicinal chemistry perspective, evaluate their potential in cancer therapy, and identify possible challenges for future advancement.

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Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation

Cited by 22 publications

References 56 publications

A novel STING agonist with systemic and durable anti‐tumour activity

A novel STING agonist with systemic and durable anti‐tumour activity

Lipid‐based nanoparticles as drug delivery systems for cancer immunotherapy

Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

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