Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides
Guodong Liu, Ruilin Hou, Lijuan Xu, Xinqi Zhang, Jianyu Yan, Chengguo Xing, Ke Xu, Chunlin Zhuang
Abstract
Directly inhibiting the Keap1–Nrf2 protein–protein interaction has been investigated as a promising strategy to activate Nrf2 for anti-inflammation. We previously reported a naphthalensulfonamide Keap1–Nrf2 inhibitor NXPZ-2, but have not determined the exact binding mode with Keap1. This symmetric naphthalenesulfonamide compound has relatively low solubility. Herein, we first determined a crystal complex (resolution: 2.3 Å) of human Keap1 Kelch domain with NXPZ-2. Further optimizations on the solvent exposed region obtained asymmetric naphthalenesulfonamides and three crystal structures of Keap1 in complex with designed compounds. Among them, the asymmetric piperazinyl-naphthalenesulfonamide 6k with better aqueous solubility showed the best KD2 value of 0.21 μM to block the interaction. The productions of ROS and NO and the expression of TNF-α were inhibited by 6k in the in vitro model. This compound could relieve inflammations by significantly increasing the Nrf2 nuclear translocation in the LPS-induced ALI model with promising pharmacokinetic properties.