Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism

被引：206

作者：

Marcotte, Douglas ^{[1
]}

Zeng, Weike ^{[1
]}

Hus, Jean-Christophe ^{[1
]}

McKenzie, Andres ^{[1
]}

Hession, Cathy ^{[1
]}

Jin, Ping ^{[1
]}

Bergeron, Chris ^{[1
]}

Lugovskoy, Alexey ^{[1
,4
]}

Enyedy, Istvan ^{[1
]}

Cuervo, Hernan ^{[1
,5
]}

Wang, Deping ^{[1
]}

Atmanene, Cedric ^{[2
]}

Roecklin, Dominique ^{[2
]}

Vecchi, Malgorzata ^{[1
]}

Vivat, Valerie ^{[2
]}

Kraemer, Joachim ^{[3
]}

Winkler, Dirk ^{[3
]}

Hong, Victor ^{[1
,6
]}

Chao, Jianhua ^{[1
]}

Lukashev, Matvey ^{[1
]}

Silvian, Laura ^{[1
]}

机构：

[1] Biogen Idec Inc, Drug Discovery, Cambridge, MA 02142 USA

[2] NoValiX, Illkirch Graffenstaden, France

[3] Evotec AG, Hamburg, Germany

[4] Merrimack Pharmaceut, Cambridge, MA 02141 USA

[5] Celgene Corp, Bedford, MA 02421 USA

[6] Keimyung Univ, Taegu, South Korea

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 14期

关键词：

Nrf2; Keap1; Protein-protein interaction inhibitor; Oxidative stress; ESI-MS; X-ray crystallography; DLG MOTIFS; PROTEINS; BINDING; MODEL; ETGE;

D O I：

10.1016/j.bmc.2013.04.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：4011 / 4019

页数：9

共 23 条

[1] Mitochondria, oxidants, and aging [J].

Balaban, RS ;

Nemoto, S ;

Finkel, T .

CELL, 2005, 120 (04) :483-495

[2]

Beamer LJ, 2005, ACTA CRYSTALLOGR D, V61, P1335, DOI [10.1107/S0907444905022626, 10.1107/S090744905022626]

[3] Kinetic Analyses of Keap1-Nrf2 Interaction and Determination of the Minimal Nrf2 Peptide Sequence Required for Keap1 Binding Using Surface Plasmon Resonance [J].

Chen, Yu ;

Inoyama, Daigo ;

Ah-Ng Tony Kong ;

Beamer, Lesa J. ;

Hu, Longqin .

CHEMICAL BIOLOGY & DRUG DESIGN, 2011, 78 (06) :1014-1021

[4] A HOT-SPOT OF BINDING-ENERGY IN A HORMONE-RECEPTOR INTERFACE [J].

CLACKSON, T ;

WELLS, JA .

SCIENCE, 1995, 267 (5196) :383-386

[5] NMRPIPE - A MULTIDIMENSIONAL SPECTRAL PROCESSING SYSTEM BASED ON UNIX PIPES [J].

DELAGLIO, F ;

GRZESIEK, S ;

VUISTER, GW ;

ZHU, G ;

PFEIFER, J ;

BAX, A .

JOURNAL OF BIOMOLECULAR NMR, 1995, 6 (03) :277-293

[6] Coot:: model-building tools for molecular graphics [J].

Emsley, P ;

Cowtan, K .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2126-2132

[7] Probing the energetics of dissociation of carbonic anhydrase-ligand complexes in the gas phase [J].

Gao, JM ;

Wu, QYQ ;

Carbeck, J ;

Lei, QP ;

Smith, RD ;

Whitesides, GM .

BIOPHYSICAL JOURNAL, 1999, 76 (06) :3253-3260

[8]

Goddard T.D, SPARKY 3

[9] A Small-Molecule Inducer of the Antioxidant Response Element [J].

Hur, Wooyoung ;

Sun, Zheng ;

Jiang, Tao ;

Mason, Daniel E. ;

Peters, Eric C. ;

Zhang, Donna D. ;

Luesch, Hendrik ;

Schultz, Peter G. ;

Gray, Nathanael S. .

CHEMISTRY & BIOLOGY, 2010, 17 (05) :537-547

[10] Dihydro-CDDO-Trifluoroethyl Amide (dh404), a Novel Nrf2 Activator, Suppresses Oxidative Stress in Cardiomyocytes [J].

Ichikawa, Tomonaga ;

Li, Jinqing ;

Meyer, Colin J. ;

Janicki, Joseph S. ;

Hannink, Mark ;

Cui, Taixing .

PLOS ONE, 2009, 4 (12)

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