The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is believed to combat both oxidative stress and inflammation as a promising strategy to treat chronic diseases. Recently, directly inhibiting the protein–protein interaction (PPI) between Nrf2 and Kelch-like ECH associated protein 1 (Keap1) has emerged as an attractive strategy to activate Nrf2 in organisms. The current development of Keap1-Nrf2 PPI inhibitors is mainly based on the interaction between Keap1 and the Nrf2 ETGE motif. However, a group of proteins that feature an ETGE motif similar to that of Nrf2 have emerged as new substrates of Keap1 over the past decade. In this Perspective, we focus on the potential off-target actions of current Keap1-Nrf2 PPI inhibitors and discuss their impact on future drug development. We also propose that a DLGex-based strategy aiming to inhibit the Keap1-Nrf2 DLGex interaction would help the development of small molecules with better target selectivity.

中文翻译：

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新兴的Kelch样ECH相关蛋白1（Keap1）的底物蛋白和Keap1-核因子类胡萝卜素2相关因子2（Nrf2）蛋白-蛋白质相互作用的小分子抑制剂的发展的潜在挑战。

作为治疗慢性疾病的一种有前途的策略，核因子类红细胞2相关因子2（Nrf2）的激活被认为可以对抗氧化应激和炎症。最近，直接抑制Nrf2和类似Kelch的ECH相关蛋白1（Keap1）之间的蛋白相互作用（PPI）已成为激活生物体中Nrf2的诱人策略。Keap1-Nrf2 PPI抑制剂的当前发展主要是基于Keap1和Nrf2 ETGE基序之间的相互作用。然而，在过去的十年中，具有类似Nrf2的ETGE基序的一组蛋白质已成为Keap1的新底物。在此观点中，我们重点介绍了当前Keap1-Nrf2 PPI抑制剂的潜在脱靶作用，并讨论了它们对未来药物开发的影响。