具有全新Nrf2-ARE诱导机制的小分子的设计及其对非可控性炎症相关疾病治疗的探索

Uncontrolled inflammation is tightly correlated with a series of systematic diseases including cancer, neurodegenerative diseases et al., no effective therapeutic or preventive agents have been obtained till now. This project aims at the possibility of treating uncontrolled inflammation through activating Nrf2-ARE pathway using small molecular inducers. Based on the 1,2,4-dioxazole inducers which are identified from previous studies, we will design and synthesize novel compounds through combining anti-inflammatory fragments and scaffold reconstruction strategy. The structure-activity relationship and structure-property relationship of the target compounds will be summarized in order to reveal the structural properties that match the inflammatory microenvironment and to enlarge the recognition of the chemical space of Nrf2-ARE inducers. Combining the techniques from genomics, proteomics, chemical biology and molecular biology, the inducers will be used as molecular probe to identify novel regulatory mechanism and target in the whole Nrf2 controlling system. The results will help us form a deeply insight into the regulation of Nrf2 pathway. Through the project, we will answer three critic scientific questions: 1) what kind of chemical property fits the best to inflammatory microenvironment? 2) Is there any unmined mechanism and target in Nrf2 regulatory pathways? 3) Is it an effective strategy in treating uncontrolled inflammation through activating Nrf2-ARE pathway by small molecular inducers?

非可控性炎症与包括恶性肿瘤、神经退行性疾病等在内的一系列重大疾病密切相关，目前尚无有效的防治药物。本项目旨在探索“通过小分子诱导剂激活Nrf2-ARE通路进而调控非可控性炎症”的可行性，以前期发现的1,2,4-恶二唑类Nrf2-ARE诱导剂为基础，通过抗炎结构片段结合分子骨架重构策略，设计并合成骨架多样性的目标化合物，探索其构效关系及构性关系，发现能够最优适配于炎性微环境理化特征的分子骨架，扩大对Nrf2-ARE诱导剂化学空间的认知；随后以其为分子探针，结合基因组及蛋白质组学、化学生物学、分子生物学技术，寻找其调控Nrf2的全新途径及靶标，深化对病理及生理环境下Nrf2整体调控网络及分子机制的认知。通过本项目的研究回答三个科学问题：1）何种结构特征与调控炎性微环境直接相关？2）Nrf2整体调控网络中是否存在尚未知晓的关键调控途径及靶标？3）通过Nrf2-ARE通路能否有效防治非可控性炎症？

非可控性炎症与恶性肿瘤、神经退行性疾病等多种重大疾病密切相关，目前尚无有效的防治药物。本项依托前期基础，围绕申请人已发现的1,2,4-噁二唑类Nrf2-ARE激活剂骨架，通过骨架重构策略，设计并合成骨架多样性的目标化合物，探索其构效关系及构性关系，获得Nrf2激活剂优选分子。随后化学生物学、分子生物学等技术，对优选分子的体内外活性及生物机制开展研究。本项目共获得结构全新的Nrf2-ARE小分子激活剂145个，完成了其构效关系总结。对其中部分活性优异的化合物，从完成构质关系研究和分子理化性质的优化，在此基础上，从化学结构角度初步阐明了本类结构与Nrf2-ARE信号通路激活和炎症调节的关联。本项目完成了对优选分子调控 Nrf2-ARE信号通路的生物机制研究，分析了优选分子与其关键靶标Keap1、AChE、BChE等的分子结合模式，为后续进一步发展结构全新的多功能Nrf2-ARE激活剂提供了重要的设计依据。本项目通过体内外药效评价，表明噁二唑类Nrf2-ARE小分子激活剂能够在实验动物层面有效调节炎症水平，对肿瘤、阿尔茨海默症等系统疾病发挥防治作用，可望成为重要的药物靶点。本项目共发表SCI收录论文20篇，其中影响因子大于5的研究论文4篇；申请国家发明专利7项。在此基础上，本项目获得了具备良好类药性的候选分子3个，目前正在进一步开展其成药性研究，这也将为后续的成果转化奠定基础。本项目达到了预期的各项研究指标，并将成为申请人在该研究方向深入研究的全新起点。