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

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 K_d 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.