Structure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction Inhibitor
Structure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction Inhibitor
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纳摩尔Keap1-Nrf2蛋白-蛋白相互作用抑制剂的构效关系及构效关系及探索性体内评价
DOI：
10.1021/acs.jmedchem.5b00185
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发表时间：
2015-08-27
影响因子：
7.3
通讯作者：
You, Qi-Dong
中科院分区：
文献类型：
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作者：
Jiang, Zheng-Yu;Xu, Li-Li;You, Qi-Dong
直接干扰Keap1-Nrf2蛋白相互作用(PPI)是激活Nrf2的有效途径。利用本课题组报道的高效的Keap1-Nrf2 PPI抑制剂，我们对环系统的结构、活性和构效关系进行了初步的研究，以改善类药物的性能。化合物18E的侧链苯环上含有对乙酰氨基取代基，是平衡PPI抑制活性、理化性质和细胞Nrf2活性的最佳选择。用18E进行的细胞实验表明，Keap1-Nrf2 PPI抑制剂可以激活Nrf2，并以Nrf2依赖的方式诱导Nrf2下游蛋白的表达。通过体内探索性实验进一步评价18E对脂多糖攻击小鼠的抗炎作用。初步结果表明，18E可降低内毒素诱导的循环促炎细胞因子水平，减轻炎症反应。
Directly disrupting the Keap1-Nrf2 protein protein interaction (PPI) is an effective way to activate Nrf2. Using the potent Keap1-Nrf2 PPI inhibitor that was reported by our group, we conducted a preliminary investigation of the structure activity and structure property relationships of the ring systems to improve the drug-like properties. Compound 18e, which bore p-acetamido substituents on the side chain phenyl rings, was the best choice for balancing PPI inhibition activity, physicochemical properties, and cellular Nrf2 activity. Cell-based experiments with 18e showed that the Keap1-Nrf2 PPI inhibitor can activate Nrf2 and induce the expression of Nrf2 downstream proteins in an Nrf2-dependent manner. An exploratory in vivo experiment was carried out to further evaluate the anti-inflammatory effects of 18e in a LPS-challenged mouse model. The primary results indicated that 18e could reduce the level of circulating pro-inflammatory cytokines induced by LPS and relieve the inflammatory response.