Development of small molecules targeting Nrf2 pathway for treatment of Colitis

描述(申请人提供)：溃疡性结肠炎(UC)是一种慢性炎症性疾病的粘膜和粘膜下层的结肠。虽然UC的发病机制是多因素和特发性的，但越来越多的证据表明，促炎介质产生过量的活性氧物种(ROS)，可导致氧化损伤，从而导致UC患者的氧化应激。由Cureveda创始人和其他人进行的使用基因敲除小鼠模型进行的概念验证临床前研究表明，选择性激活转录因子信号是一种潜在的治疗癌症的策略。 氧化应激相关的炎症性疾病。转录因子Nrf2在调节抗氧化剂防御和先天免疫反应方面发挥了重要作用。此外，我们的初步证据表明，增强Nrf2可以抑制Th-17引发的炎症。Cureveda的创始人已经确定了一种有效的Nrf2信号小分子激活剂，Veda-1209，它具有治疗UC的潜力。我们假设，通过降低氧化反应和增加抗氧化反应的速度，VEDA-1209减少了炎症相关的损伤。拟议的第一阶段项目旨在评估Veda-1209用于治疗溃烂和药效学研究，并通过在小鼠模型中评估氧化应激、炎症和组织损伤的标记物来确定其治疗效果。积极的结果将支持VEDA-1209在第二阶段SBIR的进一步临床前开发。

DESCRIPTION (provided by applicant): Ulcerative colitis (UC) is a chronic inflammatory disorder of the mucosa and submucosa of the colon. Although the pathogenesis of UC is multifactorial and idiopathic, a growing body of evidence suggests that proinflammatory mediators produce excess reactive oxygen species (ROS) which can cause oxidative damage resulting in oxidative stress in UC patients. Proof-of-concept preclinical studies using knockout mouse models conducted by Cureveda's founders and others have demonstrated that the selective activation of transcription factor signaling is a potential strategy for the treatment of oxidative-stress-related inflammatory diseases. The transcription factor Nrf2 has emerged as a central player in regulating antioxidant defenses and innate immune response. In addition, our preliminary evidence suggests that augmenting Nrf2 inhibits Th-17 driven inflammation. Cureveda's founders have identified a potent small molecule activator of Nrf2 signaling, VEDA-1209, which has potential as a therapeutic for UC. We hypothesize that, by reducing the rates of oxidative reactions and increasing the rates of antioxidative reactions, VEDA-1209 reduces inflammation-related injury. The proposed Phase I project aims to evaluate VEDA-1209 for the treatment of ulcerative and pharmacodynamic studies and determining its therapeutic efficacy by evaluating markers of oxidative stress, inflammation and tissue injury in the mouse model. Positive outcomes will support further preclinical development of VEDA-1209 in phase II SBIR.