Keap Calm, and Carry on Covalently

Abstract

The Nrf2-Keap1 system plays a major role in cellular defense against oxidative stress. Upon exposure to electrophiles, the cysteine-rich protein Keap1 is covalently modified, and it is this modification of Keap1 that allows the accumulation and subsequent nuclear translocation of Nrf2 where it induces the transcription of over 100 protective genes. This mechanism can be exploited in drug discovery approaches to diseases such as chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), asthma, and neurodegenerative diseases like multiple sclerosis (MS) and Parkinson's, utilizing the modification of Keap1 by electrophiles, compounds that would not normally be considered useful in drug discovery programs. This Perspective discusses the development of potential therapies based on potent electrophiles, such as isothiocyanates and Michael acceptors, that, far from being associated with toxic events, can actually initiate a range of beneficial protective pathways.

Synthesis, evaluation, and metabolism of novel [6]-shogaol derivatives as potent Nrf2 activators

“…5,6 Therefore, Nrf2 is a potential target for many chronic diseases, such as chronic kidney disease, asthma, neurodegenerative diseases, and cancer. [7][8][9][10][11][12][13] It is known that small molecules Nrf2 activators, such as sulforaphane (SFN), 14 curcumin, 15 and chalcone derivatives, 16 have been identified as cancer chemopreventive agents. Screening for Nrf2 activators would lead to the discovery of new pharmaceuticals for oxidative stress-associated chronic diseases.…”

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

“…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. Thus, directly disrupting the Keap1-Nrf2 protein−protein interaction (PPI) has been regarded as an innovative strategy to activate Nrf2.…”

Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway

“…19,20 In fact, there are a number of electrophilic small molecules that are known to activate Nrf2, and these have been reviewed in detail elsewhere. 21,22 Some of the more prominent members of this class include the isothiocyanate sulforaphane (1) , derived from cruciferous vegetables like broccoli; and dimethyl fumarate (2) , a recently approved therapeutic for multiple sclerosis (see Chart 1). Another member of this class is the cyanoenone bardoxolone methyl (3) , an agent currently in clinical trials for pulmonary arterial hypertension in the United States and for diabetic nephropathy in Japan.…”