Abstract：
Most BTB-containing E3 ligases homodimerize to recognize a single substrate by engaging multiple degrons, represented by E3 ligase KEAP1 dimer and its substrate NRF2. Inactivating KEAP1 to hinder ubiquitination-dependent NRF2 degradation activates NRF2. While various KEAP1 inhibitors have been reported, all reported inhibitors bind to KEAP1 in a monovalent fashion and activate NRF2 in a lagging manner. Herein, we report a unique bivalent KEAP1 inhibitor, biKEAP1 (3), that engages cellular KEAP1 dimer to directly release sequestered NRF2 protein, leading to an instant NRF2 activation. 3 promotes the nuclear translocation of NRF2, directly suppressing proinflammatory cytokine transcription. Data from in vivo experiments showed that 3, with unprecedented potency, reduced acute inflammatory burden in several acute inflammation models in a timely manner. Our findings demonstrate that the bivalent KEAP1 inhibitor can directly enable sequestered substrate NRF2 to suppress inflammatory transcription response and dampen various acute inflammation injuries.
摘要：
大多数含BTB的E3连接酶均二聚化以通过接合多个degrons来识别单个底物，由E3连接酶KEAP1二聚体及其底物NRF2表示。使KEAP1失活以阻止泛素化依赖性NRF2降解激活NRF2。虽然已经报道了各种KEAP1抑制剂，所有报道的抑制剂都以单价方式与KEAP1结合,并以滞后方式激活NRF2.在这里，我们报道了一种独特的二价KEAP1抑制剂，biKEAP1(3),使细胞KEAP1二聚体直接释放螯合的NRF2蛋白，导致瞬间NRF2激活。3促进NRF2的核转位，直接抑制促炎细胞因子的转录。来自体内实验的数据表明，3，具有前所未有的效力，及时降低几种急性炎症模型的急性炎症负担。我们的发现表明，二价KEAP1抑制剂可以直接使螯合的底物NRF2抑制炎症转录反应并抑制各种急性炎症损伤。
