Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry and Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain.
Victor Babes National Institute of Pathology, Bucharest, Romania.
Nat Rev Drug Discov. 2019 Apr;18(4):295-317. doi: 10.1038/s41573-018-0008-x.
The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.
转录因子 NF-E2 p45 相关因子 2（NRF2；由 NFE2L2 编码）及其主要负调节剂，E3 连接酶衔接子 Kelch 样 ECH 相关蛋白 1（KEAP1），在维持氧化还原、代谢和蛋白质稳态以及调节炎症方面至关重要。因此，NRF2 的激活为许多病理提供了细胞保护作用，包括肺部和肝脏的慢性疾病；自身免疫性、神经退行性和代谢疾病；以及癌症的发生。一种 NRF2 激活剂已获得临床批准，几种基于半胱氨酸的传感器 KEAP1 的亲电子修饰物及其与 NRF2 相互作用的抑制剂目前正在临床开发中。然而，关于靶标特异性、药效学特性、疗效和安全性仍然存在挑战。
