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Review
. 2012 Jul;32(4):687-726.
doi: 10.1002/med.21257. Epub 2012 May 1.

Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents

Sadagopan Magesh  1 , Yu Chen, Longqin Hu
Affiliations
Review

Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents

Sadagopan Magesh et al. Med Res Rev. 2012 Jul.

Abstract

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.

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Figures

Figure 1
Figure 1
Organization and functions of structure domains in Keap1. The reactive key cysteine residues and nuclear import signaling site (white down arrow) are indicated. The redox sensitive cysteine residues are marked with (*).
Figure 2
Figure 2
Organization and functions of structure domains in Nrf2. The reactive key cysteine residues, nuclear import (white down arrow), and nuclear export (white up arrow) signaling sites are indicated.
Figure 3
Figure 3
The proposed regulatory mechanisms of Keap1-Nrf2-ARE pathway. (A) Under basal conditions, Nrf2 binds to Keap1 through ETGE (‘hinge’) and DLG (‘latch’) motifs (two-site recognition), and Nrf2 is constantly ubiquitinated by Keap1-Cul3-Ligase complex and degraded in the 26S proteasome (B) Under induced conditions, electrophilic modification of specific Keap1 cysteines induces a conformational change in Keap1 that disrupts the low affinity interaction with DLG (‘latch’) and consequently affects ubiquitination of Nrf2 (‘hinge’ and ‘latch’ model). Alternatively, inducers can cause the dissociation of Keap1-Cul3 complex, which prevents the ubiquitination and subsequent proteasomal degradation of Nrf2.
Figure 4
Figure 4
The proposed reaction mechanism of Michael addition reactions between Michael acceptors and cysteine sulfhydryl groups in Keap1.
Figure 5
Figure 5
Diphenols and their oxidation products that contain electrophilic Michael acceptors.
Figure 6
Figure 6
The binding mode of 16mer Nrf2 peptide in the Kelch domain of Keap1 (PDB Code: 2FLU). The bound protein residues (three letter code) involved in the interaction are depicted on the surface. Nrf2 peptide is displayed as stick models and interacting amino acid E79 and E82 residues are indicated.
Figure 7
Figure 7
The contacts between the 16mer Nrf2 peptide and the Kelch domain of Keap1 (PDB Code: 2FLU). Keap1 residues are displayed as stick models and Nrf2 peptide resides are displayed as line. Intermolecular hydrogen bonds are given with their distances (Å). Residues are not involved in binding are omitted for clarity.
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