2. Academic Validation
  3. Discovery of β-amino acid substituted naphthalene sulfonamide derivatives as potent Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) protein-protein interaction inhibitors for ulcerative colitis management

Discovery of β-amino acid substituted naphthalene sulfonamide derivatives as potent Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) protein-protein interaction inhibitors for ulcerative colitis management

  • Eur J Med Chem. 2025 Feb 13:288:117384. doi: 10.1016/j.ejmech.2025.117384.
Ziquan Zhao 1,  Hongjin Lu 1,  Junjie Wang 1,  Tingting Wu 1,  Shicheng Xu 1,  Yuxin Ge 1,  Qidong You 2,  Zhengyu Jiang 3,  Mengchen Lu 4
Affiliations

Affiliations

  • 1 Jiang Su Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Jiang Su Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University Medical College, Suzhou, 215123, China. Electronic address: youqd@163.com.
  • 3 Jiang Su Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: jiangzhengyucpu@163.com.
  • 4 Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University Medical College, Suzhou, 215123, China. Electronic address: mclu@suda.edu.cn.
PMID: 39965408 DOI: 10.1016/j.ejmech.2025.117384
Abstract

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular defense system against oxidative insults. Directly inhibiting the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 protein-protein interaction (PPI) has emerged as a promising approach to activate Nrf2 for the treatment of diseases associated with oxidative stress. Herein, we identified β-amino acids as privileged structural fragments for designing novel naphthalene sulfonamide-based Keap1-Nrf2 PPI inhibitors. Comprehensive structure-activity relationship (SAR) exploration identified compound 19 as the optimal inhibitor with an IC50 of 0.55 μM for disrupting the Keap1-Nrf2 interaction and a Kd of 0.50 μM for binding to Keap1. Further studies demonstrated that 19 effectively activated the Nrf2-regulated cytoprotective system and provided protective effects against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in both in vitro and in vivo models. These findings highlight the potential of β-amino acid substituted naphthalene sulfonamide Keap1-Nrf2 inhibitor 19 as a prospective therapeutic agent for UC via Keap1 targeting.

Keywords

Keap1−Nrf2 pathway; Oxidative stress; Protein−protein interaction inhibitor; Ulcerative colitis.

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