转录因子核因子红细胞生成相关因子2（NRF2）被认为是第二期抗氧化反应的主要调节因子。它控制着大量与氧化应激，炎症和蛋白质稳态相关的细胞保护基因以及其他过程。这些通路的激活在多种疾病中都有描述，包括癌症、心血管、呼吸、肾脏、消化、代谢、自身免疫和神经退行性疾病。鉴于越来越多的人对发现新的NRF2活化剂的兴趣，因为它在临床应用中的应用，最初的努力专注于开发电泳药物，能够通过对半胱氨酸残基的共价修饰，诱导NRF2核蛋白聚积的作用，以靶向自然抑制剂蛋白Kelch-like ECH-associated protein 1（KEAP1）。然而，这些药物的离靶效应促使发展了一种创新的策略，即搜索KEAP1-NRF2蛋白-蛋白相互作用（PPI）抑制剂。这些创新的活化剂被提出以更加选择性地靶向NRF2，从而导致潜在的改进药物，适用于目前正在调查的各种疾病。在本综述中，我们总结了迄今为止已知的KEAP1-NRF2 PPI抑制剂及其设计基础，重点介绍了它们各自相互作用的最重要特征。我们还讨论了最有前途的化合物描述的临床前药理特性。©2022年作者。由Wiley Periodicals LLC出版的药物研究评论。

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is considered the master regulator of the phase II antioxidant response. It controls a plethora of cytoprotective genes related to oxidative stress, inflammation, and protein homeostasis, among other processes. Activation of these pathways has been described in numerous pathologies including cancer, cardiovascular, respiratory, renal, digestive, metabolic, autoimmune, and neurodegenerative diseases. Considering the increasing interest of discovering novel NRF2 activators due to its clinical application, initial efforts were devoted to the development of electrophilic drugs able to induce NRF2 nuclear accumulation by targeting its natural repressor protein Kelch-like ECH-associated protein 1 (KEAP1) through covalent modifications on cysteine residues. However, off-target effects of these drugs prompted the development of an innovative strategy, the search of KEAP1-NRF2 protein-protein interaction (PPI) inhibitors. These innovative activators are proposed to target NRF2 in a more selective way, leading to potentially improved drugs with the application for a variety of diseases that are currently under investigation. In this review, we summarize known KEAP1-NRF2 PPI inhibitors to date and the bases of their design highlighting the most important features of their respective interactions. We also discuss the preclinical pharmacological properties described for the most promising compounds.© 2022 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.