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  • Longqin Hu

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Project Title2012-044 Novel Small Molecule Inhibitors and their Applications in Anti-inflammatory and Oxidative Stress-Related Disease Therapeutics
Track Code2012-044
Websitehttp://otc.rutgers.edu/
Short Description

      Scientists at Rutgers University have designed a series of novel small molecule direct inhibitors to the Keap1-Nrf2 complex. Using state-of-the-art fluorescence-based high throughput screening assays, X-ray crystallography, computational chemistry and surface plasma resonance (SPR), chemical libraries were screened to discover and confirm new compounds which directly trigger this pathway. The optimized direct inhibitors can be used as important pharmacological probes to study and elucidate Keap1-Nrf2-ARE cytoprotective signaling, in addition to being used as potent cancer chemopreventative agents.  In summary, these small molecule inhibitors are direct potent disruptors of Keap1-Nrf2 interaction, which are potentially free
of various undesirable effects.

Abstract

Oxidative stress and inflammation are byproducts of normal cellular processes as well as underlying contributors of chronic pathological conditions such as cancer, diabetes, Alzheimer's and Parkinson's. Kelch-like ECH-associated protein 1 ("Keap1"), Nuclear Factor Erythroid 2-related factor 2 ("Nrf2") and Antioxidant Response Elements) ("ARE"), are three major cellular components that induce an adaptive response for oxidative stress which can otherwise lead to many inflammatory diseases. Disruption of the Keap1-Nrf2 protein-protein interaction releases the transcription factor Nrf2, which upregulates a number of antioxidant and cytoprotective enzymes. Therefore targeting this signaling pathway is an attractive strategy to discover preventative and therapeutic agents for disease conditions. Unfortunately, all current small molecule inhibitors of Keap1-Nrf2 interaction are indirect inhibitors and their effects are potentially irreversible and non-selective.

Scientists at Rutgers University have designed a series of novel small molecule direct inhibitors to the Keap1-Nrf2 complex. Using state-of-the-art fluorescence-based high throughput screening assays, X-ray crystallography, computational chemistry and surface plasma resonance (SPR), chemical libraries were screened to discover and confirm new compounds which directly trigger this pathway. The optimized direct inhibitors can be used as important pharmacological probes to study and elucidate Keap1-Nrf2-ARE cytoprotective signaling, in addition to being used as potent cancer chemopreventative agents. In summary, these small molecule inhibitors are direct potent disruptors of Keap1-Nrf2 interaction, which are potentially free of various undesirable effects.

 
TagsAnti-Inflammatory Therapeutic, Antioxidants, cancer therapeutics, Oxidative Stress-related Disease Treatments
 
Posted DateJun 11, 2012 10:14 AM

Researcher

Name
Longqin Hu

Manager

Name
Stuart Palmer

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