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Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate

Dimethyl fumarate (DMF) is an electrophilic compound previously called BG-12 and marketed under the name Tecfidera (®). It was approved in 2013 by the US Food and Drug Administration and the European Medicines Agency for the treatment of relapsing multiple sclerosis. One mechanism of action of DMF i...

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Autores principales: Satoh, Takumi, Lipton, Stuart
Formato: Online Artículo Texto
Lenguaje:English
Publicado: F1000 Research Limited 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730864/
https://www.ncbi.nlm.nih.gov/pubmed/29263788
http://dx.doi.org/10.12688/f1000research.12111.1
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author Satoh, Takumi
Lipton, Stuart
author_facet Satoh, Takumi
Lipton, Stuart
author_sort Satoh, Takumi
collection PubMed
description Dimethyl fumarate (DMF) is an electrophilic compound previously called BG-12 and marketed under the name Tecfidera (®). It was approved in 2013 by the US Food and Drug Administration and the European Medicines Agency for the treatment of relapsing multiple sclerosis. One mechanism of action of DMF is stimulation of the nuclear factor erythroid 2-related factor 2 (NRF2) transcriptional pathway that induces anti-oxidant and anti-inflammatory phase II enzymes to prevent chronic neurodegeneration. However, electrophiles such as DMF also produce severe systemic side effects, in part due to non-specific S-alkylation of cysteine thiols and resulting depletion of glutathione. This mini-review presents the present status and future strategy for NRF2 activators designed to avoid these side effects. Two modes of chemical reaction leading to NRF2 activation are considered here. The first mode is S-alkylation (covalent reaction) of thiols in Kelch-like ECH-associated protein 1 (KEAP1), which interacts with NRF2. The second mechanism involves non-covalent pharmacological inhibition of protein-protein interactions, in particular domain-specific interaction between NRF2 and KEAP1 or other repressor proteins involved in this transcriptional pathway. There have been significant advances in drug development using both of these mechanisms that can potentially avoid the systemic side effects of electrophilic compounds. In the first case concerning covalent reaction with KEAP1, monomethyl fumarate and monoethyl fumarate appear to represent safer derivatives of DMF. In a second approach, pro-electrophilic drugs, such as carnosic acid from the herb Rosmarinus officinalis, can be used as a safe pro-drug of an electrophilic compound. Concerning non-covalent activation of NRF2, drugs are being developed that interfere with the direct interaction of KEAP1-NRF2 or inhibit BTB domain and CNC homolog 1 (BACH1), which is a transcriptional repressor of the promoter where NRF2 binds.
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spelling pubmed-57308642017-12-19 Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate Satoh, Takumi Lipton, Stuart F1000Res Review Dimethyl fumarate (DMF) is an electrophilic compound previously called BG-12 and marketed under the name Tecfidera (®). It was approved in 2013 by the US Food and Drug Administration and the European Medicines Agency for the treatment of relapsing multiple sclerosis. One mechanism of action of DMF is stimulation of the nuclear factor erythroid 2-related factor 2 (NRF2) transcriptional pathway that induces anti-oxidant and anti-inflammatory phase II enzymes to prevent chronic neurodegeneration. However, electrophiles such as DMF also produce severe systemic side effects, in part due to non-specific S-alkylation of cysteine thiols and resulting depletion of glutathione. This mini-review presents the present status and future strategy for NRF2 activators designed to avoid these side effects. Two modes of chemical reaction leading to NRF2 activation are considered here. The first mode is S-alkylation (covalent reaction) of thiols in Kelch-like ECH-associated protein 1 (KEAP1), which interacts with NRF2. The second mechanism involves non-covalent pharmacological inhibition of protein-protein interactions, in particular domain-specific interaction between NRF2 and KEAP1 or other repressor proteins involved in this transcriptional pathway. There have been significant advances in drug development using both of these mechanisms that can potentially avoid the systemic side effects of electrophilic compounds. In the first case concerning covalent reaction with KEAP1, monomethyl fumarate and monoethyl fumarate appear to represent safer derivatives of DMF. In a second approach, pro-electrophilic drugs, such as carnosic acid from the herb Rosmarinus officinalis, can be used as a safe pro-drug of an electrophilic compound. Concerning non-covalent activation of NRF2, drugs are being developed that interfere with the direct interaction of KEAP1-NRF2 or inhibit BTB domain and CNC homolog 1 (BACH1), which is a transcriptional repressor of the promoter where NRF2 binds. F1000 Research Limited 2017-12-14 /pmc/articles/PMC5730864/ /pubmed/29263788 http://dx.doi.org/10.12688/f1000research.12111.1 Text en Copyright: © 2017 Satoh T and Lipton S http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review
Satoh, Takumi
Lipton, Stuart
Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate
title Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate
title_full Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate
title_fullStr Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate
title_full_unstemmed Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate
title_short Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate
title_sort recent advances in understanding nrf2 as a druggable target: development of pro-electrophilic and non-covalent nrf2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730864/
https://www.ncbi.nlm.nih.gov/pubmed/29263788
http://dx.doi.org/10.12688/f1000research.12111.1
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