KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential.
KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential.
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DOI：
10.1002/med.21925
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发表时间：
2023-01
影响因子：
13.3
通讯作者：
中科院分区：
文献类型：
--
作者：
转录因子核因子红系2相关因子2 （NRF2）被认为是II期抗氧化反应的主要调节因子。它控制着与氧化应激、炎症和蛋白质稳态等过程相关的大量细胞保护基因。这些通路的激活已经在许多疾病中被描述，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。由于NRF2的临床应用，人们对发现新型NRF2激活剂的兴趣日益浓厚，因此，研究人员最初致力于开发亲电药物，通过对半胱氨酸残基进行共价修饰，靶向NRF2的天然抑制蛋白Kelch样ECH相关蛋白1 (KEAP1)，从而诱导NRF2的核积累。然而，这些药物的脱靶效应促使了一种创新策略的发展，即寻找KEAP1‐NRF2蛋白-蛋白相互作用（PPI）抑制剂。这些创新的激活剂被提议以一种更有选择性的方式靶向NRF2，从而导致潜在的改进药物应用于目前正在研究的各种疾病。在这篇综述中，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的临床前药理学性质。
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.
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影响因子：
7.3
作者：
Begnini F;Poongavanam V;Over B;Castaldo M;Geschwindner S;Johansson P;Tyagi M;Tyrchan C;Wissler L;Sjö P;Schiesser S;Kihlberg J
通讯作者：
Kihlberg J
影响因子：
11.4
作者：
Casares L;Moreno R;Ali KX;Higgins M;Dayalan Naidu S;Neill G;Cassin L;Kiib AE;Svenningsen EB;Minassi A;Honda T;Poulsen TB;Wiel C;Sayin VI;Dinkova-Kostova AT;Olagnier D;de la Vega L
通讯作者：
de la Vega L
影响因子：
3.9
作者：
Gacesa R;Lawrence KP;Georgakopoulos ND;Yabe K;Dunlap WC;Barlow DJ;Wells G;Young AR;Long PF
通讯作者：
Long PF
影响因子：
16
作者：
Baird, Liam;Swift, Sam;Lleres, David;Dinkova-Kostova, Albena T.
通讯作者：
Dinkova-Kostova, Albena T.
影响因子：
3.8
作者：
Chen, Ke;Huang, Liuliu;Shen, Bin
通讯作者：
Shen, Bin