Structure-activity relationships of 1,4-bis(arylsulfonamido)-benzene or naphthalene-N,N'-diacetic acids with varying C2-substituents as inhibitors of Keap1-Nrf2 protein-protein interaction.
Structure-activity relationships of 1,4-bis(arylsulfonamido)-benzene or naphthalene-N,N'-diacetic acids with varying C2-substituents as inhibitors of Keap1-Nrf2 protein-protein interaction.
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DOI：
10.1016/j.ejmech.2022.114380
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发表时间：
2022-07-05
影响因子：
6.7
通讯作者：
Hu L
中科院分区：
文献类型：
--
作者：
Lee S;Abed DA;Nguyen MU;Verzi MP;Hu L
Keap 1-Nrf 2-ARE信号通路在机体响应氧化应激和维持氧化还原稳态中起重要作用。直接靶向Keap 1-Nrf 2蛋白质-蛋白质相互作用（PPI）的小分子抑制剂可以潜在地被开发成许多慢性炎症性疾病的有效预防和治疗剂。为了提高该类抑制剂的类药性能和抑制活性，设计合成了一系列在苯或萘核的C-2位具有不同取代基的1，4-二（芳基磺酰胺基）苯或萘-N，N '-二乙酸类化合物。其中，具有2-（4-氟苄氧基）基团的化合物12 d是Keap 1-Nrf 2 PPI的最有效的直接抑制剂，在荧光偏振（FP）测定中的IC 50为64.5 nM，在时间分辨荧光共振能量转移（TR-FRET）测定中的IC 50为14.2 nM。细胞生物学检测结果显示，12 d显著提高了Nrf 2下游基因GSTM 3、HMOX 2和NQO 1的mRNA水平。在C2位置具有不同O-连接片段的新支架的发现提供了进一步修饰Keap 1-Nrf 2 PPI抑制剂的化学结构以改善其药代动力学、疗效和安全性的机会。
The Keap1-Nrf2-ARE pathway plays an important role in responding to oxidative stress and maintaining the redox homeostasis. Small molecule inhibitors targeting directly the Keap1-Nrf2 protein-protein interaction (PPI) can potentially be developed into effective preventive and therapeutic agents for numerous chronic inflammatory diseases. To improve the drug-like properties and inhibitory potency of these inhibitors, a series of 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N'-diacetic acids with varying substituents at C-2 position of the benzene or naphthalene core were designed and synthesized. Among them, compound 12d with 2-(4-fluorobenzyloxy) group was the most potent direct inhibitor of Keap1-Nrf2 PPI with an IC50 of 64.5 nM in the fluorescent polarization (FP) assay and 14.2 nM in a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Moreover, cell-based biological assay showed that 12d significantly increased the mRNA levels of Nrf2 downstream genes, GSTM3, HMOX2 and NQO1, through Nrf2 activation. The discovery of the new scaffolds possessing diverse O-linked fragments at the C2 position offers opportunities to further modify the chemical structures of Keap1-Nrf2 PPI inhibitors to improve their pharmacokinetic, efficacy and safety profiles.
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DOI：
10.1056/nejmoa1306033
发表时间：
2013-12-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
de Zeeuw D;Akizawa T;Audhya P;Bakris GL;Chin M;Christ-Schmidt H;Goldsberry A;Houser M;Krauth M;Lambers Heerspink HJ;McMurray JJ;Meyer CJ;Parving HH;Remuzzi G;Toto RD;Vaziri ND;Wanner C;Wittes J;Wrolstad D;Chertow GM;BEACON Trial Investigators
通讯作者：
BEACON Trial Investigators
影响因子：
16
作者：
Baird, Liam;Swift, Sam;Lleres, David;Dinkova-Kostova, Albena T.
通讯作者：
Dinkova-Kostova, Albena T.
DOI：
10.1016/j.bbrc.2013.02.065
发表时间：
2013-03-29
影响因子：
3.1
作者：
Baird, Liam;Dinkova-Kostova, Albena T.
通讯作者：
Dinkova-Kostova, Albena T.
影响因子：
7.3
作者：
Davies, Thomas G.;Wixted, William E.;Kerns, Jeffrey K.
通讯作者：
Kerns, Jeffrey K.
纳摩尔Keap1-Nrf2蛋白-蛋白相互作用抑制剂的构效关系及构效关系及探索性体内评价
影响因子：
7.3
作者：
Jiang, Zheng-Yu;Xu, Li-Li;You, Qi-Dong
通讯作者：
You, Qi-Dong