Validation of non-electrophile Nrf2 activators for WTC relevant pulmonary indications

针对 WTC 相关肺部适应症的非亲电子 Nrf2 激活剂的验证

• 批准号: 10064367
• 负责人: Michael Darin Cameron
• 金额: $ 49.99万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064367
• 关键词: Validation; non; electrophile; Nrf2; activators

The current proposal is designed to lay the foundation for a medicinal-chemistry driven translational project to optimize a non-electrophilic Nrf2 activator. Nrf2 is the body's master regulator for defense against oxidative stress. Nrf2 is a transcription factor and is activated in oxidative environments through inhibition of the ubiquitin ligase Keap1. In oxidative environments, oxidation of redox-active cysteines on the surface of Keap1 leads to its inactivation. This increases Nrf2 levels and up-regulates the expression of Nrf2 target genes, which represent an array of proteins designed to mitigate oxidative stress. Traditionally Nrf2 activators were weak oxidants that covalently react with the intended Keap1 cysteine but also modify numerous unintended proteins. Nrf2 activators have had narrow therapeutic windows due to toxicity resulting from their non-specific reactivity. This proposal is unique in the use of non-electrophilic Nrf2 activators discovered in our lab that disrupt Nrf2 ubiquitination without covalent modification through disruption of protein-protein interactions. We have seen excellent induction of Nrf2 target genes in vivo without signs of toxicity at the tested doses. Nrf2 is an attractive target for pulmonary fibrotic diseases. Disease models have demonstrated that oxidative stress plays a key role in the development of pulmonary fibrosis and modulation of Nrf2 signaling chemically and genetically impact disease progression. World Trade Center responders have two to five times elevated risk of pulmonary fibrosis, which increases with intensity and duration of exposure to WTC dust/debris and work on the debris pile. WTC responders are younger than the average pulmonary fibrosis patient, and improved treatments that slow or stop the progression of pulmonary fibrosis and increase life span are needed. WTC-relevant pulmonary models will be used to test the lead Nrf2 activator as a stand- alone treatment and in concert with a recently approved drug for idiopathic pulmonary fibrosis. There is no cure for pulmonary fibrosis, and while two new therapies have shown a benefit in slowing the decline of forced vital capacity (the volume of air that can be forcibly exhaled after taking a deep breath), they have not demonstrated increased lifespan. Improved therapies working independently or providing additive benefit when given together with current medications would have a significant impact on human health.

目前的提议旨在为药物化学驱动的翻译奠定基础 优化非亲电NRF2激活剂的项目。NRF2是人体防御的主要调节器 氧化应激。NRF2是一种转录因子，在氧化环境中通过抑制 泛素连接酶Keap1。在氧化环境中，氧化还原活性半胱氨酸在表面的氧化 Keap1导致其失活。这增加了Nrf2水平并上调了Nrf2靶标的表达 基因，它代表了一系列旨在减轻氧化应激的蛋白质。传统的Nrf2激活剂 是弱氧化剂，与预期的Keap1半胱氨酸发生共价反应，但也修饰了许多 意外的蛋白质。NRF2激活剂由于其毒性而具有狭窄的治疗窗口 非特异性反应性。这项提议在使用非亲电的NRF2激活剂方面是独一无二的，在我们的 通过破坏蛋白质-蛋白质而在没有共价修饰的情况下破坏NRF2泛素化的实验室 互动。我们已经看到在体内很好地诱导了Nrf2靶基因，没有毒性的迹象 测试过的剂量。 NRF2是治疗肺纤维化疾病的一个有吸引力的靶点。疾病模型已经证明 氧化应激在肺纤维化的发生发展及Nrf2信号调节中的关键作用 从化学和基因上影响疾病的进展。世界贸易中心的响应人员有两到五次 肺纤维化风险增加，随着暴露于WTC的强度和时间的延长而增加 灰尘/碎屑和碎屑堆上的工作。WTC的应答者比平均肺纤维化患者更年轻 患者，以及延缓或阻止肺纤维化进展并延长生命的改进治疗 跨度是必需的。与WTC相关的肺模型将用于测试领先的Nrf2激活剂作为标准- 单独治疗，并与最近批准的治疗特发性肺纤维化的药物联合使用。没有 治疗肺纤维化，虽然两种新的治疗方法在减缓强迫的下降方面显示出好处 肺活量(深吸一口气后可以用力呼出的气量)，他们没有 显示出延长了寿命。改进的治疗方法独立起作用或提供附加益处 如果与目前的药物一起服用，将对人类健康产生重大影响。