Polar Recognition Group Study of Keap1-Nrf2 Protein-Protein Interaction Inhibitors
Polar Recognition Group Study of Keap1-Nrf2 Protein-Protein Interaction Inhibitors
复制标题
Keap1-Nrf2 蛋白质-蛋白质相互作用抑制剂的极性识别组研究
DOI：
10.1021/acsmedchemlett.5b00407
复制
发表时间：
2016-09-01
影响因子：
4.2
通讯作者：
Jiang, Zheng-Yu
中科院分区：
文献类型：
--
作者：
Lu, Meng-Chen;Tan, Shi-Jie;Jiang, Zheng-Yu
Directly disrupting the Keap1-Nrf2 protein protein interaction (PPI) has emerged as an attractive way to activate Nrf2, and Keap1-Nrf2 PPI inhibitors have been proposed as potential agents to relieve inflammatory and oxidative stress diseases. In this work, we investigated the diacetic moiety around the potent Keap1-Nrf2 PPI inhibitor DDO1018 (2), which was reported by our group previously. Exploration of bioisosteric replacements afforded the ditetrazole analog 7, which maintains the potent PPI inhibition activity (IC50 = 15.8 nM) in an in vitro fluorescence polarization assay. Physicochemical property determination demonstrated that ditetrazole replacement can improve the drug-like property, including elevation of pK(a), log D, and transcellular permeability. Additionally, 7 is more efficacious than 2 on inducing the expression of Nrf2-dependent gene products in cells. This study provides an alternative way to replace the diacetic moiety and occupy the polar subpockets in Keap1, which can benefit the subsequent development of Keap1-Nrf2 PPI inhibitor.
