Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents.
Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents.
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DOI：
10.1002/med.21257
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发表时间：
2012-07
影响因子：
13.3
通讯作者：
Hu, Longqin
中科院分区：
文献类型：
--
作者：
Magesh, Sadagopan;Chen, Yu;Hu, Longqin
关键词：
Keap1-Nrf2-ARE途径是细胞抵御氧化应激和异物损伤最重要的防御机制之一。Nrf2信号的激活诱导ARE依赖的多种解毒和抗氧化防御酶和蛋白的转录调控。Keap1-Nrf2-ARE信号已成为预防和治疗氧化应激相关疾病和疾病的一个有吸引力的靶点，这些疾病包括癌症、神经退行性疾病、心血管疾病、代谢和炎症性疾病。在过去的几十年里，已经开发了许多Nrf2诱导剂，其中一些目前正在进行临床试验。最近，Nrf2的过度激活被认为与癌症的进展以及对癌症化疗的耐药性有关。因此，Nrf2抑制剂可能被用于提高癌症治疗的有效性。本文就Keap1-Nrf2-ARE途径的信号机制、与疾病的相关性以及目前已知的小分子调节剂类作一综述。我们还讨论了Keap1-Nrf2相互作用的几个方面，基于Nrf2的多肽抑制剂的设计，以及目前用于发现Keap1-Nrf2相互作用的直接抑制剂的筛选试验。
Keap1-Nrf2-ARE pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of Nrf2 signaling induces the transcriptional regulation of ARE-dependent expression of various detoxifying and antioxidant defense enzymes and proteins. Keap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic and inflammatory diseases. Over the last few decades, numerous Nrf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, over-activation of Nrf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, Nrf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of Keap1-Nrf2-ARE pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of Keap1-Nrf2 interaction, Nrf2-based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of Keap1-Nrf2 interaction.
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发表时间：
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影响因子：
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作者：
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期刊：
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影响因子：
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