Small Molecule Modulators of Keap1‐Nrf2‐ARE Pathway as Potential Preventive and Therapeutic Agents

Abstract

Keap1-Nrf2-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, over-activation 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.

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…The recent evidence suggested that the involvement of ROS in HD pathogenesis is by dysfunctioning of the mitochondrial complex II (Calkins et al 2005). In the primary phase of HD, the focus is on the activation of the astrocyte and microglia by an overexpression of the vital cytoprotective genes via the Keap1-Nrf2-ARE system by Nrf2 agonist; this might protect the brain injury caused by the ROS (Magesh et al 2012). Activation of the Keap1-Nrf2-ARE pathway by small molecules in astrocytes accelerates the resistance of neurons to the non-excitotoxic glutamate toxicity (Kraft et al 2004).…”

“…The Keap1-targeted inhibition mechanism has been mainly carried out by inhibitors that could interrupt the cross-talk between the former and Nrf2 (Magesh et al 2012). One of the methodologies of reduction in the Keap1 population, hampering the redox balance, involves the dimerisation of Keap1 to prevent Nrf2 binding.…”

Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease

“…Organisms regulate the production and scavenging of free radicals spontaneously or passively via various signaling pathways. The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway, a significant signaling pathway in the detoxification of ROS in the brain region [19,20] , represents an important cellular defense mechanism against oxidative stress damage [21] . This pathway controls an array of endogenous cellular defense mechanisms against oxidative stress [22] .…”

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

“…sulforaphane, chalcone, and curcumin. 12 These traditional Nrf2-ARE activators are all electrophiles that form a covalent bond to a cysteine residue in the target Keap1 protein. 13 The electrophilic nature of these activators could increase the uncertainty in further clinical development.…”