Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction.
Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction.
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DOI：
10.1016/j.bmcl.2013.03.013
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发表时间：
2013-05-15
影响因子：
2.7
通讯作者：
Munoz, Benito
中科院分区：
文献类型：
--
作者：
Hu, Longqin;Magesh, Sadagopan;Chen, Lin;Wang, Lili;Lewis, Timothy A.;Chen, Yu;Khodier, Carol;Inoyama, Daigo;Beamer, Lesa J.;Emge, Thomas J.;Shen, Jian;Kerrigan, John E.;Ah-Ng Tony Kong;Dandapani, Sivaraman;Palmer, Michelle;Schreiber, Stuart L.;Munoz, Benito
利用均匀荧光偏振法对MLPCN文库进行高通量筛选（HTS），发现一个小分子是Keap1-Nrf2蛋白-蛋白相互作用的首个直接抑制剂。HTS分子有三个手性中心；闪光和手性色谱分离相结合表明，keap1的结合活性主要存在于一个名为ML334 （LH601A）的立体异构体(SRS)-5中，其结合活性至少是其他立体异构体的100倍。四个顺式异构体的立体化学是用x射线晶体学指定的，并用立体定向合成证实。（SRS）-5在ARE基因报告试验和Nrf2核易位试验中都具有功能活性。（SRS）-5和Keap1之间的立体特异性结合以及初步但易于处理的结构-活性关系支持其作为我们正在进行的优化的先导。
A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100× more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure-activity relationships support its use as a lead for our ongoing optimization.
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DOI：
10.1158/1940-6207.capr-10-0296
发表时间：
2011-03
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Egner PA;Chen JG;Wang JB;Wu Y;Sun Y;Lu JH;Zhu J;Zhang YH;Chen YS;Friesen MD;Jacobson LP;Muñoz A;Ng D;Qian GS;Zhu YR;Chen TY;Botting NP;Zhang Q;Fahey JW;Talalay P;Groopman JD;Kensler TW
通讯作者：
Kensler TW
影响因子：
4.2
作者：
Steel, Richard;Cowan, Jonathan;Payerne, Estelle;O'Connell, Maria A.;Searcey, Mark
通讯作者：
Searcey, Mark
DOI：
10.1073/pnas.90.7.2965
发表时间：
1993-04-01
影响因子：
11.1
作者：
PRESTERA, T;HOLTZCLAW, WD;TALALAY, P
通讯作者：
TALALAY, P
影响因子：
9.3
作者：
Lau, Alexandria;Villeneuve, Nicole F.;Sun, Zheng;Wong, Pak Kin;Zhang, Donna D.
通讯作者：
Zhang, Donna D.
影响因子：
3.4
作者：
Christov, Christo;Gonzalez-Bulnes, Patricia;Giraldo, Jesus
通讯作者：
Giraldo, Jesus