Discovery of potent Keap1-Nrf2 Protein-Protein Interaction Inhibitor Based on Molecular Binding Determinants Analysis and structure-guided modification
Keap1 is known to mediate the ubiquitination of Nrf2,a master regulator of the antioxidant response.Directly interrupting the Keap1-Nrf2 interaction has been emerged as a promising strategy to develop novel class of antioxidant,antiinflammatory,and anticancer agents.Based on the molecular binding determinants analysis of Keap1,we successfully designed and characterized the most potent protein-protein interaction (PPI) inhibitor of Keap1-Nrf2,compound 2,with KD value of 3.57 nM binding to Keap1 for the first time to single digit nanomolar.Compound 2 can effectively disrupt the Nrf2-Keap1 interaction with an EC50 of 28.6 nM in the fluorescence polarization assay.It can also activate the Nrf2 transcription activity in the cell-based ARE-luciferase reporter assay in a dose-dependent manner.The qRT-PCR results of Nrf2 transcription targets gave the consistent results.These results confirm direct and highly efficient interruption of the Keap1-Nrf2 PPI can be fully achieved by small molecules.
Hao-Peng Sun Zheng-Yu Jiang Meng-Chen Lu Qi-Dong You
Jiang Su Key Laboratory of Drug Design and Optimization,China Pharmaceutical University,Nanjing 2100 Jiang Su Key Laboratory of Drug Design and Optimization,China Pharmaceutical University,Nanjing 2100
国内会议
南京
英文
1-17
2014-06-10（万方平台首次上网日期，不代表论文的发表时间）