Document Detail

Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents.
MedLine Citation:
PMID:  22549716     Owner:  NLM     Status:  MEDLINE    
Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elements (ARE) pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of Nrf2 signaling induces the transcriptional regulation of ARE-dependent expression of various detoxifying and antioxidant defense enzymes and proteins. Keap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic, and inflammatory diseases. Over the last few decades, numerous Nrf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, overactivation of Nrf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, Nrf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of Keap1-Nrf2-ARE pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of Keap1-Nrf2 interaction, Nrf2-based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of Keap1-Nrf2 interaction.
Sadagopan Magesh; Yu Chen; Longqin Hu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review     Date:  2012-05-01
Journal Detail:
Title:  Medicinal research reviews     Volume:  32     ISSN:  1098-1128     ISO Abbreviation:  Med Res Rev     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-10     Completed Date:  2012-11-09     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  8103150     Medline TA:  Med Res Rev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  687-726     Citation Subset:  IM    
Copyright Information:
© 2012 Wiley Periodicals, Inc.
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MeSH Terms
Anti-Inflammatory Agents / therapeutic use
Antineoplastic Agents / therapeutic use
Antioxidants / metabolism*,  therapeutic use
Hypoglycemic Agents / therapeutic use
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors,  metabolism*
NF-E2-Related Factor 2 / antagonists & inhibitors,  metabolism*
Neuroprotective Agents / therapeutic use
Oxidative Stress
Response Elements
Signal Transduction*
Grant Support
CA125868/CA/NCI NIH HHS; CA133791/CA/NCI NIH HHS; MH093197/MH/NIMH NIH HHS; R01 CA133791/CA/NCI NIH HHS; R01 CA133791-01A2/CA/NCI NIH HHS; R01 CA133791-02/CA/NCI NIH HHS; R01 CA133791-03/CA/NCI NIH HHS; R03 CA125868/CA/NCI NIH HHS; R03 CA125868-01A1/CA/NCI NIH HHS; R03 CA125868-02/CA/NCI NIH HHS; R03 MH093197/MH/NIMH NIH HHS; R03 MH093197-01/MH/NIMH NIH HHS; R03 MH093197-02/MH/NIMH NIH HHS
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Antineoplastic Agents; 0/Antioxidants; 0/Hypoglycemic Agents; 0/Intracellular Signaling Peptides and Proteins; 0/NF-E2-Related Factor 2; 0/Neuroprotective Agents

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