更新于：2024-11-01

NOX1

更新于：2024-11-01

基本信息

别名

GP91-2、mitogenic oxidase (pyridine nucleotide-dependent superoxide-generating)、Mitogenic oxidase 1

+ [12]

简介

NOH-1S is a voltage-gated proton channel that mediates the H(+) currents of resting phagocytes and other tissues. It participates in the regulation of cellular pH and is blocked by zinc. NOH-1L is a pyridine nucleotide-dependent oxidoreductase that generates superoxide and might conduct H(+) ions as part of its electron transport mechanism, whereas NOH-1S does not contain an electron transport chain.

关联

项与 NOX1 相关的药物

Setanaxib

靶点

NOX1 x NOX4

作用机制

NOX1抑制剂 [+1]

在研机构

Calliditas Therapeutics AB [+2]

原研机构

Calliditas Therapeutics France SAS

在研适应症

复发性头颈部鳞状细胞癌 [+2]

非在研适应症

2型糖尿病 [+4]

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

NADPH oxidase gene therapy(Généthon)

靶点

NOX1

作用机制

NOX1刺激剂 [+1]

在研机构

Genethon [+1]

原研机构

Genethon

在研适应症

慢性肉芽肿病

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

GKT771

靶点

NOX1

作用机制

NOX1抑制剂

在研机构

Calliditas Therapeutics France SAS

原研机构

Calliditas Therapeutics France SAS

在研适应症

结直肠癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 NOX1 相关的临床试验

NCT06274489 / Recruiting临床1/2期

A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of the NOX1/4 Inhibitor Setanaxib in Patients With Alport Syndrome

The purpose of the study is to learn about the safety and tolerability of setanaxib in subjects with Alport syndrome, when added to their standard of care treatment. The study will assess how safe setanaxib is when compared to placebo. Study participants will be asked if they are experiencing any side effects at each study visit. In addition, tests in blood, urine and other examinations will be used to look at the safety of setanaxib. The study will also measure how well setanaxib works in comparison to a placebo, by measuring urine protein and certain markers in the blood and urine. The concentration of setanaxib in the blood will also be measured throughout the course of the study.
Setanaxib is planned for use together with the current standard of care to hopefully provide additional therapeutic benefits by preserving kidney function.
The study will be conducted at multiple research sites in the UK, Spain, and Czech Republic. Eligible participants will be randomly assigned to receive either setanaxib or placebo. Setanaxib dose level will depend on age and all participants will receive their standard of care in addition to setanaxib or placebo. The study consists of a Screening period of up to 4 weeks, a 24-week Treatment period and a 4- week Follow-up period.

开始日期2023-11-27

申办/合作机构

Calliditas Therapeutics AB

NCT05323656 / Active, not recruiting临床2期

A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Setanaxib, When Administered With Pembrolizumab, in Patients With Recurrent or Metastatic SCCHN

The primary objective of this study is to compare the change in tumour size per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in recurrent or metastatic SCCHN patients treated with setanaxib and pembrolizumab versus patients treated with placebo and pembrolizumab.

开始日期2022-04-06

申办/合作机构-

EUCTR2021-004627-33-ES / Unknown status临床2期

A Phase 2, Randomised, Double-Blind, Placebo-Controlled, Proof-of-Concept Study to Evaluate the Efficacy, Safety, and Tolerability, and Effects on Tumour Biomarkers of the NOX1/4 Inhibitor Setanaxib, when Administered with the PD-1 Inhibitor Pembrolizumab, in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

开始日期2022-03-08

申办/合作机构-

100 项与 NOX1 相关的临床结果

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100 项与 NOX1 相关的转化医学

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0 项与 NOX1 相关的专利（医药）

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1,930

项与 NOX1 相关的文献（医药）

2024-11-01·Redox Biology

NoxO1 regulates EGFR signaling by its interaction with Erbin

Article

作者: Schader, Tim ; Hebchen, Maureen ; Graumann, Johannes ; Spaeth, Manuela ; Müller, Niklas ; Hebchen, Dana Maureen ; Schröder, Katrin

NADPH oxidase organizer 1 (NoxO1) is a scaffold cytoplasmic subunit of the reactive oxygen species (ROS) forming Nox1 complex and involved in angiogenesis, differentiation, and atherosclerosis. We found that overexpression of NoxO1 without simultaneous overexpression of any other component of the active Nox1 complex inhibited EGF-induced wound closure and signaling, while NoxO1 KO yielded the opposite effect. Accordingly, we hypothesize NoxO1 to exert Nox1 independent functions. Using the BioID technique, we identified ErbB2 interacting protein (Erbin) as novel interaction partner of NoxO1. Colocalization of NoxO1 with EGFR, as well as with Erbin validated this finding. EGF treatment interrupted colocalization of NoxO1 and EGFR. EGF mediated kinase activation was delayed in NoxO1 overexpressing cells, while knockout of NoxO1 had the opposite effect. In conclusion, Erbin was identified as a novel NoxO1 interacting protein. Through the subsequent interaction of NoxO1 and EGFR, NoxO1 interferes with EGF signaling. The results of this study suggest a potential role of NoxO1 as an adaptor protein with functions beyond the well-established enabling of Nox1 mediated ROS formation.

2024-11-01·Free Radical Biology and Medicine

Prohibitin 2 confers NADPH oxidase 1-mediated cytosolic oxidative signaling to promote gastric cancer progression by ERK activation

Article

作者: Meng, Li

Oxidative signaling plays a dual role in tumor initiation and progression to malignancy; however, the regulatory mechanisms of oxidative stress in gastric cancer remain to be explored. In this study, we discovered that Prohibitin 2 (PHB2) specifically regulates cytosolic reactive oxygen species production in gastric cancer and facilitates its malignant progression. Previously, we found that PHB2 is upregulated in gastric cancer, correlating with increased tumorigenicity of gastric cancer cells and poor patient prognosis. Here, we discovered that PHB2 expression correlates with the activation of the ERK/MAPK cascade, positively regulating the top gene NADPH oxidase 1 (NOX1) within this pathway. Further mechanistic investigation reveals that PHB2 enhances NOX1 transcription by interacting with the transcription factor C/EBP-beta and promoting its translocation into the nucleus, resulting in elevated intracellular oxidative signaling driven by NOX1, which subsequently activates ERK. Therefore, we propose that targeting PHB2-C/EBP-beta-NOX1-mediated cytosolic oxidative stress could offer a promising therapeutic avenue for combating gastric cancer malignant progression.

2024-11-01·Cytokine

Apocynin alleviates thioacetamide-induced acute liver injury: Role of NOX1/NOX4/NF-κB/NLRP3 pathways

Article

作者: Sharawy, Maha H ; El-Kashef, Dalia H. ; Abdel-Rahman, Noha ; Sharawy, Maha H. ; El-Kashef, Dalia H

The liver has a distinctive capacity to regenerate, yet severe acute injury can be life-threatening if not treated appropriately. Inflammation and oxidative stress are central processes implicated in the pathophysiology of acute livery injury. NOX isoforms are important enzymes for ROS generation, NF-κB and NLRP3 activation, its inhibition could be vital in alleviating acute liver injury (ALI). Here in our study, we used apocynin, a natural occurring potent NOX inhibitor, to exploreits potential protective effect against thioacetamide (TAA)-induced ALI through modulating crucial oxidative and inflammatory pathways. Rats were injected once with TAA (500 mg/kg/i.p) and treated with apocynin (10 mg/kg/i.p) twice before TAA challenge. Sera and hepatic tissues were collected for biochemical, mRNA expression, western blot analysis and histopathological assessments. Pretreatment with apocynin improved liver dysfunction evidenced by decreased levels of aminotransferases, ALP, GGT and bilirubin. Apocynin reduced mRNA expression of NOX1 and NOX4 which in turn alleviated oxidative stress, as shown by reduction in MDA and NOx levels, and elevation in GSH levels andcatalase and SOD activities. Moreover, apocynin significantly reduced MPO gene expression. We also demonstrate that apocynin ameliorated inflammation through activating IκBα and suppressing IKKα, IKKβ, NF-κBp65 and p-NF-κBp65, IL-6 andTNF-α. Additionally, apocynin potentiated the gene expression of anti-inflammatory IL-10 and reduced levels of hepatic NLRP3, Caspase-1 and IL-1β. These results suggest that apocynin protects against ALI in association with the inhibition of NOX1 and NOX4 and regulating oxidative and inflammatory pathways.

项与 NOX1 相关的新闻（医药）

2024-10-21

·药时代

揭秘癌症中的ROS：从捣蛋分子到治疗明星的奇妙旅程

氧化还原稳态的失衡是各种人类疾病的根源之一，特别是ROS（活性氧）水平的异常升高，被证实对肿瘤的发生与发展具有关键推动作用。鉴于此，科学家们将通过调节ROS及其复杂的调控网络作为抗癌治疗的新策略。近期，该领域取得了突破性进展，不仅揭示了新氧化还原信号通路，还发现了生物分子相分离现象在ROS调控中的独特作用。本文将重点讨论靶向ROS的癌症治疗策略与药物，并对未来研究方向进行展望。 01 ROS的基本概念和生成 ROS指生物体内由氧分子直接或间接转化而来的具有高度化学活性的含氧物质，包括超氧阴离子、过氧化氢、羟自由基等。它们广泛存在于生物体内，在调节生物过程成发挥重要作用。 ROS在生物体内的生成途径主要包括线粒体呼吸链、酶促反应（如NADPH氧化酶能催化生成ROS）、外源性因素（如紫外线辐射、化学物质）等方面。为了维持生物体内的氧化还原稳态，细胞通过抗氧化酶系统（超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GPx）等催化ROS的分解和清除）、非酶抗氧化剂（非酶抗氧化剂：如维生素C、维生素E、谷胱甘肽（GSH）等能与ROS反应并中和其活性）等机制来控制和调节ROS的水平[1]。 02 ROS介导的信号传导翻译后修饰（PTMs）是ROS调节细胞信号传导的主要机制，ROS通过修饰氧化还原敏感残基影响其目标蛋白的功能。ROS直接介导半胱氨酸硫醇基和蛋氨酸硫残基的氧化修饰，进而影响蛋白质的结构和稳定性、蛋白质之间的相互作用、亚细胞定位等，导致其各自功能的改变。这些变化可以影响组蛋白和DNA的表观遗传修饰，从而影响转录过程。ROS通过PTMs调节对氧化还原敏感的转录因子进而影响mRNA和非编码RNA（ncRNA）的转录[2]。图1 ROS介导的信号传递过程 03 靶向ROS的癌症治疗策略在癌症中靶向ROS能够实现对肿瘤细胞的选择性治疗，且对正常细胞的毒性相对较低。根据作用机制，靶向ROS的癌症治疗策略可分为两类：靶向ROS生成机制和靶向氧化还原适应机制[3]。图2 靶向癌症中ROS的治疗策略 04 靶向ROS生成机制癌细胞由于其异常的代谢活动和遗传背景，往往处于较高的氧化应激状态，即细胞内ROS水平相对较高。这种内在的ROS应激是癌细胞生物学特性的一部分，与它们的增殖、生存和耐药性密切相关。当针对癌细胞中的ROS生成机制进行靶向治疗时通过增加细胞内的ROS水平，加剧氧化应激，对细胞内的DNA、蛋白质和脂质等生物分子造成广泛损伤，当这种损伤达到一定程度时，会触发癌细胞的凋亡或坏死机制，导致不可逆的细胞损伤和死亡，或者通过减少ROS水平使其降低到不足以支持癌细胞的正常增殖。多种药物和化合物可以通过上调ROS产生酶（如NOX5）的活性来增加ROS的生成。例如，多靶点酪氨酸激酶抑制剂安罗替尼（anlotinib）能够在体外诱导鳞状细胞癌细胞中的O2•−生成和凋亡。一些氧化还原调节剂能够在癌细胞中作为促氧化剂，促进ROS的生成，而在正常组织中则作为抗氧化剂，保护组织免受氧化应激的损害，这种选择性作用机制使得它们在癌症治疗中具有潜在的应用价值。NADPH氧化酶（NOX）是一种能够催化生成ROS的酶，在癌症中某些致癌转化，如RAS基因驱动的NOX表达上调，会导致ROS的生成增加。ROS的过量生成与多种癌症的恶性进展有关。GKT831是一种有效的双NADPH氧化酶（NOX）抑制剂，主要针对NOX1和NOX4亚型，GKT831能够抑制ROS的生成，并使肿瘤细胞对辐射更加敏感。 05 靶向氧化还原适应机制野生型p53在ROS应激下被激活，导致细胞周期停滞或凋亡，这是一种防止细胞损伤和癌变的重要机制。而某些p53突变后则能在应激条件下促进细胞存活，这也是癌细胞逃避凋亡的一种策略。突变型p53通过上调ROS清除系统（如NRF2介导的途径）和激活抗凋亡信号（如NF-κB）来适应ROS应激。抑制内源性抗氧化剂或其上游调控分子成为破坏p53突变细胞氧化还原适应机制的手段。表1 靶向癌症中活性氧（ROS）并具有治疗潜力的新药物 06 结语针对癌症中的活性氧（ROS）进行靶向治疗是一项充满前景的治疗策略，它带来了新机遇与挑战。ROS应激下的免疫反应对癌症具有双刃剑作用，既能通过细胞毒性免疫细胞抑制肿瘤生长，也能通过免疫抑制细胞促进癌细胞增殖。ROS与炎症细胞因子相互刺激，放大炎症信号，影响肿瘤生长或导致系统性代谢异常。未来研究应综合考虑癌细胞和免疫系统，基于患者的癌症阶段、ROS应激和免疫功能，实现抗氧化剂和氧化还原调节的个性化治疗。 Ref. [1] Wu K, El Zowalaty AE, Sayin VI, Papagiannakopoulos T. The pleiotropic functions of reactive oxygen species in cancer. Nat Cancer. 2024 Mar;5(3):384-399. [2] An X, Yu W, Liu J, Tang D, Yang L, Chen X. Oxidative cell death in cancer: mechanisms and therapeutic opportunities. Cell Death Dis. 2024 Aug 1;15(8):556. [3] Glorieux C, Liu S, Trachootham D, Huang P. Targeting ROS in cancer: rationale and strategies. Nat Rev Drug Discov. 2024 Aug;23(8):583-606. 封面图来源：123rf 版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 喜讯频传！1天3家，礼新、若弋、平方和官宣融资成功！百裕制药成功出海！雅本化学新研发大楼启用典礼圆满举行三期临床失败后，吉利德决定自愿撤回适应症 “创新是金，赛出新高”——金赛药业2024首届研发日圆满落幕点击查看更多精彩！

信使RNA

2024-07-29

·药明康德

治疗肝脏疾病，小分子疗法达到2b期临床主要终点

▎药明康德内容团队编辑 Calliditas Therapeutics日前宣布，其2b期临床试验TRANSFORM试验达到了主要终点，显示出在两种剂量下，在研疗法setanaxib与安慰剂组相比，显著改善患有原发性胆汁性胆管炎（PBC）且肝硬度增加的患者的碱性磷酸酶（ALP）水平。 TRANSFORM试验是一项随机双盲、含安慰剂对照的2b期研究，调查了剂量为1200 mg或1600 mg的setanaxib在24周中的治疗效果。分析基础数据集包括76名患有PBC且肝硬度增加的患者。试验中超过40%的患者同时接受了至少两种背景治疗。接受setanaxib治疗的患者在主要终点ALP上显示出显著的改善，在1600 mg组中为19%，在1200 mg组中为14%，并且在24周时在FibroScan评估的肝硬度上显示出积极趋势。Setanaxib治疗总体上耐受性良好，治疗出现不良事件（TEAE）以及严重TEAE的数量在治疗组和安慰剂组之间相似。因不良事件导致研究中止的频率在接受setanaxib治疗的患者中高于安慰剂组。 ▲Setanaxib的临床开发项目（图片来源：Calliditas Therapeutics官网） Setanaxib是一种NOX1/4抑制剂。NOX1和NOX4是产生活性氧（ROS）的酶，这些酶通过导致氧化应激、炎症和组织重塑，在纤维化疾病的发展中起着关键作用。它们参与成纤维细胞的活化和细胞外基质蛋白的合成，导致瘢痕组织的形成。因此，靶向NOX1和NOX4提供了一种针对纤维化疾病的治疗策略，有可能比广泛的抗氧化治疗具有更少的副作用，并且能够减缓疾病的进展。除了治疗PBC，setanaxib还在临床试验中接受评估，治疗头颈部鳞状细胞癌、特发性肺纤维化、以及阿尔波特综合征（Alport Syndrom）。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] Calliditas announces positive TRANSFORM Phase 2b topline data in primary biliary cholangitis. Retrieved July 26, 2024, from https://www.prnewswire.com/news-releases/calliditas-announces-positive-transform-phase-2b-topline-data-in-primary-biliary-cholangitis-302207354.html 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床结果临床2期

2024-06-25

·echemi

Emerging PBC Treatments: The Fourth Novel Therapy Set to Lead the Market

In recent years, the treatment of primary biliary cholangitis (PBC) has seen remarkable progress, with the continuous introduction of new drugs bringing good news to PBC patients worldwide. According to reports from authoritative institutions, the global PBC treatment market is thriving and is expected to experience explosive growth in the coming years. However, despite the fact that three PBC treatment drugs have already been approved, the market still has a significant unmet need, and the industry's expectations for new therapeutic drugs are becoming increasingly urgent. First, let's understand the three PBC treatment drugs currently on the market. Ursodeoxycholic acid (UDCA) is the recognized first-line treatment drug and has been widely used in clinical practice for many years. However, it is regrettable that about 40% of patients do not respond well to this treatment, leaving them in urgent need of more effective treatment options. Against this backdrop, Ocaliva and Elafibranor emerged, being approved as second-line treatment options for PBC in 2016 and 2021, respectively. The introduction of these two drugs has undoubtedly brought new hope to PBC patients. However, market competition has not stopped. Industry insiders generally believe that Seladelpar has the potential to become the fourth novel PBC drug approved globally. Seladelpar is an oral, potent, and selective PPARδ agonist, and its unique mechanism of action gives it significant advantages in regulating bile acid synthesis, inflammation, fibrosis, and lipid metabolism. Based on preclinical and clinical data, Seladelpar has demonstrated good efficacy and safety in the treatment of PBC. Currently, the drug is undergoing priority review in the United States and is expected to receive approval for marketing in August 2024. At that time, it is expected to bring a safer and more effective treatment option to PBC patients worldwide. In addition to Seladelpar, the industry is also paying attention to other PBC drug candidates in development. For example, Setanaxib is a new drug that targets NOX4 and NOX1, and it has unique potential in the field of PBC treatment. Furthermore, domestic pharmaceutical companies are also actively engaged in the development of PBC drug research, such as the dual-target peptide drug TB001 developed by a well-known pharmaceutical company. The successive launch of these candidate drugs will bring new development opportunities to the PBC treatment market. It is worth mentioning that with the advancement of technology and the depth of research, the PBC treatment field is facing unprecedented development opportunities. More and more new drugs and new technologies are emerging, bringing more treatment options to PBC patients. At the same time, as global medical standards improve and medical resources are optimized, the treatment experience of PBC patients will also be significantly improved. We have reason to believe that in the near future, PBC patients will be able to enjoy safer, more effective, and more convenient treatment services.

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