PDF(Pubmed)
Abstract：
The Keap1-Nrf2-ARE signaling pathway is an attractive therapeutic target for the prevention and treatment of oxidative stress-associated diseases by activating the cellular expression of cytoprotective enzymes and proteins. Small molecule inhibitors can directly disrupt the Keap1-Nrf2 protein-protein interaction (PPI), resulting in elevated levels of Nrf2 protein and subsequent stimulation of related antioxidant responses. Previously, we found that 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N\'-diacetic acid derivatives with an ether type C2-substituent on the benzene or naphthalene core exhibited potent inhibitory activities with IC50\'s in the submicromolar or nanomolar range. We here describe a more detailed structure-activity relationship study around the C2 substituents containing various polar linkers shedding new insight on their binding interactions with the Keap1 Kelch domain. The key observation from our findings is that the substituents at the C2-position of the benzene or naphthalene scaffold impact their inhibitory potencies in biochemical assays as well as activities in cell culture. The biochemical FP and TR-FRET assays revealed that the naphthalene derivatives 17b and 18 with an additional carboxylate at the C2 were the most active inhibitors against Keap1-Nrf2 PPI. In the cell-based assay, the two compounds were shown to be potent Nrf2 activators of the transcription of the Nrf2-dependent genes, such as HMOX2, GSTM3, and NQO1.
摘要：
Keap1-Nrf2-ARE信号通路是通过激活细胞保护酶和蛋白质的细胞表达来预防和治疗氧化应激相关疾病的有吸引力的治疗靶标。小分子抑制剂可以直接破坏Keap1-Nrf2蛋白-蛋白相互作用（PPI），导致Nrf2蛋白水平升高，随后刺激相关的抗氧化反应。以前,我们发现1,4-双(芳基磺酰氨基)苯或萘-N,在苯或萘核上具有醚型C2取代基的N'-二乙酸衍生物表现出有效的抑制活性，IC50在亚微摩尔或纳摩尔范围内。我们在这里描述了围绕包含各种极性接头的C2取代基的更详细的结构-活性关系研究，从而对它们与Keap1Kelch结构域的结合相互作用产生了新的见解。我们发现的关键观察是，苯或萘支架C2位的取代基会影响其在生化测定中的抑制效力以及在细胞培养中的活性。生化FP和TR-FRET测定显示,在C2处具有额外羧酸盐的萘衍生物17b和18是针对Keap1-Nrf2PPI的最具活性的抑制剂。在基于细胞的检测中，这两种化合物被证明是Nrf2依赖性基因转录的有效Nrf2激活剂，例如HMOX2、GSTM3和NQO1。
