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更新于：2025-05-24

RU-521

更新于：2025-05-24

概要

概要

基本信息

药物类型

小分子化药

别名

RU 320521、RU 521、RU.521

+ [2]

靶点

CGAS

作用方式

抑制剂

作用机制

CGAS抑制剂(cyclic GMP-AMP synthase inhibitors)

治疗领域

免疫系统疾病神经系统疾病遗传病与畸形+ [1]

在研适应症

Aicardi-Goutieres综合征

非在研适应症-

原研机构

Vanderbilt University School of Medicine

在研机构

Vanderbilt University School of Medicine

非在研机构-

权益机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构/序列

分子式C19H12Cl2N4O3

InChIKeyVIQXILLOJLATEF-UHFFFAOYSA-N

CAS号2262452-06-0

关联

100 项与 RU-521 相关的临床结果

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100 项与 RU-521 相关的转化医学

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100 项与 RU-521 相关的专利（医药）

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项与 RU-521 相关的文献（医药）

2025-08-01·Neural Regeneration Research

The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson’s disease

Article

作者: Zhao, Weijiang ; Quan, Wei ; Cui, Chun ; Zhang, Wei ; Li, Ting ; Wu, Jian ; Qiao, Chenmeng ; Qiao, Xinyu ; Hong, Hui ; Shen, Yanqin ; Zhou, Shengyang

JOURNAL/nrgr/04.03/01300535-202508000-00026/figure1/v/2024-09-30T120553Z/r/image-tiff Interferon regulatory factor 7 plays a crucial role in the innate immune response. However, whether interferon regulatory factor 7-mediated signaling contributes to Parkinson’s disease remains unknown. Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–induced mouse model of Parkinson’s disease and co-localizes with microglial cells. Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype. In addition, siRNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase, tumor necrosis factor α, CD16, CD32, and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1. Taken together, our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase–stimulator of interferon genes–interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson’s disease

2025-05-01·iScience

Birch pollen allergen-induced dsDNA release activates cGAS-STING signaling and type 2 immune response in mice

Article

作者: Messaoud-Nacer, Yasmine ; Chenuet, Pauline ; Rouxel, Nathalie ; Ledru, Aurélie ; Mellier, Manon ; Marquant, Quentin ; Fauconnier, Louis ; Ryffel, Bernhard ; Quesniaux, Valérie F J ; Culerier, Elodie ; Apetoh, Lionel ; Rose, Stéphanie ; Togbe, Dieudonnée

Detecting cytoplasmic or extracellular DNA from host or pathogen origin by DNA sensor cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggers immune responses with secretion of type I interferons and inflammatory cytokines. However, STING agonists function as type-2 adjuvant promoting allergic asthma. Here, we asked how cGAS/STING signaling pathway influences allergen-induced type-2 immune responses in models of allergic airway diseases induced by birch pollen extract, house dust mite, or ovalbumin plus Alum. We report increased extracellular dsDNA in the airways, together with cGAS and STING gene expression, following allergen challenge in these models, correlating dsDNA and type-2 cytokine IL-4, IL-5, and IL-13 release. Allergen-induced type-2 immune responses were reduced in cGAS- or STING-deficient mice. Further, blocking cGAS function with the specific inhibitor RU.521 protected mice from birch pollen allergen-induced airway inflammation and type-2 immune responses. Thus, DNA sensing by cGAS contributes to type-2 immune responses and may represent a therapeutic target for allergic lung inflammation.

2025-04-01·British Journal of Pharmacology

Genetic deficiency or pharmacological inhibition of cGAS–STING signalling suppresses kidney inflammation and fibrosis

Article

作者: Tran, Melanie ; Du, Hao ; Yang, Duomeng ; Jiao, Baihai ; Zhao, Yuqi ; Wang, Penghua ; Hu, Zhaoyong ; An, Changlong ; Wang, Yanlin ; Zhou, Dong

Abstract:

Background and Purpose:

Chronic kidney disease (CKD) is characterised by inflammation, which can lead to tubular atrophy and fibrosis. The molecular mechanisms are not well understood. In this study, we investigated the functional role of the cyclic GMP–AMP synthase (cGAS)– stimulator of interferon genes (STING) signalling in renal inflammation and fibrosis.

Experimental Approach:

Mice with global cGAS deficiency or global or myeloid cell‐specific STING deficiency or wild‐type mice treated with RU.521, a selective cGAS inhibitor, were used to examine the role of cGAS–STING signalling in renal inflammation and fibrosis in a preclinical model of obstructive nephropathy in vivo. Bone marrow‐derived macrophages were used to determine whether tubular epithelial cell‐derived DNA can activate cGAS–STING signalling in vitro.

Key Results:

Following obstructive injury, cGAS–STING signalling was activated in the kidneys during the development of renal fibrosis. Mice with deficiency of cGAS or STING exhibited significantly less macrophage proinflammatory activation, myofibroblast formation, total collagen deposition, and extracellular matrix (ECM) protein production in the kidneys following obstructive injury. Pharmacological inhibition of cGAS with RU.521 reduced macrophage proinflammatory activation, suppressed myofibroblast formation, and attenuated kidney fibrosis following obstructive injury. Mechanistically, cGAS–STING signalling in macrophages is activated by double‐stranded DNA released from damaged tubular epithelial cells, which induces inflammatory responses.

Conclusions and Implications:

Our study identifies the cGAS–STING signalling pathway as a critical regulator of macrophage proinflammatory activation during the development of renal fibrosis. Therefore, inhibition of cGAS–STING signalling may represent a novel therapeutic strategy for CKD.

100 项与 RU-521 相关的药物交易

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