The transcription factor NRF2 confers cellular protection by maintaining cellular redox homeostasis and proteostasis. Basal NRF2 levels are normally low due to KEAP1-mediated ubiquitylation and subsequent proteasomal degradation. KEAP1, a substrate adaptor protein of a KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, contains a critical cysteine (C151) that is modified by electrophiles or oxidants, resulting in inactivation of the E3 ligase and inhibition of NRF2 degradation. Currently, nearly all NRF2 inducers are electrophilic molecules that possess unwanted off-target effects due to their reactive nature. Here, we report a group of NRF2 inducers, ent-kaurane diterpenoid geopyxins, with and without C151 reactive electrophilic moieties. Among 16 geopyxins, geopyxin F, a non-electrophilic NRF2 activator, showed enhanced cellular protection relative to an electrophilic NRF2 activator, geopyxin C. To our knowledge, this is the first detailed structure-activity relationship study of covalent versus non-covalent NRF2 activators, showing the promise of non-covalent NRF2 activators as potential therapeutic compounds.

中文翻译：

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非共价 NRF2 激活比共价激活提供更好的细胞保护。

转录因子 NRF2 通过维持细胞氧化还原稳态和蛋白质稳态来提供细胞保护。由于 KEAP1 介导的泛素化和随后的蛋白酶体降解，基础 NRF2 水平通常较低。KEAP1 是 KEAP1-CUL3-RBX1 E3 泛素连接酶复合物的底物衔接蛋白，含有一个关键的半胱氨酸 (C151)，可被亲电子试剂或氧化剂修饰，导致 E3 连接酶失活并抑制 NRF2 降解。目前，几乎所有的 NRF2 诱导剂都是亲电子分子，由于其反应性，它们具有不需要的脱靶效应。在这里，我们报告了一组 NRF2 诱导剂，ent-kaurane 二萜类 geopyxins，具有和不具有 C151 反应性亲电基团。在 16 种 geopyxin 中，geopyxin F 是一种非亲电子 NRF2 激活剂，