title: Polar Recognition Group Study of Keap1-Nrf2 Protein-Protein Interaction Inhibitors.
abstract: 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.
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Meng-Chen
authors.initials: MC
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Shi-Jie
authors.initials: SJ
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Jian-Ai
authors.initials: JA
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Zhi-Yun
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Jiang
keywords: Keap1; Nrf2; protein−protein interaction