Small Molecule Modulators of <scp>K</scp>eap1‐<scp>N</scp>rf2‐<scp>ARE</scp> Pathway as Potential Preventive and Therapeutic Agents

<jats:title>Abstract</jats:title><jats:p><jats:styled-content style="fixed-case">K</jats:styled-content>elch‐like <jats:styled-content style="fixed-case">ECH</jats:styled-content>‐associated protein 1 (<jats:styled-content style="fixed-case">K</jats:styled-content>eap1)‐nuclear factor erythroid 2‐related factor 2 (<jats:styled-content style="fixed-case">N</jats:styled-content>rf2)‐antioxidant response elements (<jats:styled-content style="fixed-case">ARE</jats:styled-content>) pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of <jats:styled-content style="fixed-case">N</jats:styled-content>rf2 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 <jats:styled-content style="fixed-case">N</jats:styled-content>rf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, overactivation of <jats:styled-content style="fixed-case">N</jats:styled-content>rf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, <jats:styled-content style="fixed-case">N</jats:styled-content>rf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of <jats:styled-content style="fixed-case">K</jats:styled-content>eap1‐<jats:styled-content style="fixed-case">N</jats:styled-content>rf2‐<jats:styled-content style="fixed-case">ARE</jats:styled-content> pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of <jats:styled-content style="fixed-case">K</jats:styled-content>eap1–<jats:styled-content style="fixed-case">N</jats:styled-content>rf2 interaction, <jats:styled-content style="fixed-case">N</jats:styled-content>rf2‐based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of <jats:styled-content style="fixed-case">K</jats:styled-content>eap1‐<jats:styled-content style="fixed-case">N</jats:styled-content>rf2 interaction. © 2012 Wiley Periodicals, Inc. Med Res Rev., 32, No. 4, 687‐726, 2012</jats:p>