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

目前的提案旨在为药物化学驱动的转化奠定基础 项目，以优化非亲电Nrf 2激活剂。nrf 2是身体的主要调节器，用于防御 氧化应激Nrf 2是一种转录因子，在氧化环境中通过抑制 泛素连接酶Keap 1。在氧化环境中，氧化还原活性的半胱氨酸的氧化在氧化物表面上发生。 Keap 1导致其失活。这增加了Nrf 2水平并上调了Nrf 2靶基因的表达。 基因，代表了一系列旨在减轻氧化应激的蛋白质。传统的NRF 2激活剂 是弱氧化剂，与预期的Keap 1半胱氨酸共价反应，但也修饰许多 非预期蛋白质NRF 2激活剂由于其自身的毒性而具有狭窄的治疗窗。 非特异性反应。该提议在使用我们的研究中发现的非亲电Nrf 2活化剂方面是独特的。 通过破坏蛋白质-蛋白质而不经共价修饰破坏Nrf 2泛素化实验室 交互.我们已经看到Nrf 2靶基因在体内的良好诱导，而没有毒性迹象。 测试剂量 nrf 2是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展和Nrf 2信号转导的调节中起关键作用 化学和遗传影响疾病进展。世贸中心的救援人员有两到五次 肺纤维化风险升高，随着暴露于WTC的强度和持续时间增加 灰尘/碎片以及碎片堆上的工作。WTC反应者比平均肺纤维化年龄小 患者，以及减缓或停止肺纤维化进展并延长寿命的改进治疗 Span是必要的。WTC相关肺部模型将用于测试Nrf 2激活剂， 单独治疗和与最近批准的特发性肺纤维化药物联合治疗。没有 治疗肺纤维化，虽然两种新的疗法已经显示出在减缓强迫下降的好处， 肺活量（深呼吸后可以用力呼出的空气量），他们没有 显示出寿命延长。独立工作或提供额外益处的改进疗法 如果与现有药物一起使用，将对人类健康产生重大影响。

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.