2. Academic Validation
  3. Crystallography-Guided Optimizations of the Keap1-Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

Crystallography-Guided Optimizations of the Keap1-Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

  • J Med Chem. 2022 Jun 23;65(12):8289-8302. doi: 10.1021/acs.jmedchem.2c00170.
Guodong Liu 1,  Ruilin Hou 1,  Lijuan Xu 2,  Xinqi Zhang 1,  Jianyu Yan 2,  Chengguo Xing 3,  Ke Xu 4 5,  Chunlin Zhuang 1 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
  • 2 School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 3 Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States.
  • 4 Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
  • 5 Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai 200434, China.
PMID: 35687391 DOI: 10.1021/acs.jmedchem.2c00170
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.

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