Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors,Journal of Medicinal Chemistry

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Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-07-13 , DOI: 10.1021/acs.jmedchem.3c00712
Ziquan Zhao _{1,

2} , Ruitian Dong _{1,

2} , Qidong You _{1,

2} , Zhengyu Jiang _{1,

2}

Affiliation

Oxidative stress has been implicated in a wide range of pathological conditions. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a central role in regulating the cellular defense system against oxidative and electrophilic insults. Nonelectrophilic inhibition of the protein–protein interaction (PPI) between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2 has become a promising approach to activate Nrf2. Recently, multiple drug discovery strategies have facilitated the development of small-molecule Keap1–Nrf2 PPI inhibitors with potent activity and favorable drug-like properties. In this Perspective, we summarize the latest progress of small-molecule Keap1–Nrf2 PPI inhibitors from medicinal chemistry insights and discuss future prospects and challenges in this field.

中文翻译：

药物化学对小分子 Kelch 样 ECH 相关蛋白 1-核因子红细胞 2 相关因子 2 (Keap1–Nrf2) 蛋白-蛋白相互作用抑制剂开发的见解

氧化应激与多种病理状况有关。转录因子核因子红细胞 2 相关因子 2 (Nrf2) 在调节细胞防御系统对抗氧化和亲电损伤方面发挥着核心作用。对 Kelch 样 ECH 相关蛋白 1 (Keap1) 和 Nrf2 之间的蛋白-蛋白相互作用 (PPI) 进行非亲电抑制已成为激活 Nrf2 的一种有前途的方法。最近，多种药物发现策略促进了小分子 Keap1-Nrf2 PPI 抑制剂的开发，这些抑制剂具有有效的活性和良好的药物样特性。在本篇文章中，我们从药物化学角度总结了小分子Keap1-Nrf2 PPI抑制剂的最新进展，并讨论了该领域的未来前景和挑战。

更新日期：2023-07-13

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