{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:21:24Z","timestamp":1789993284318,"version":"4.0.1"},"reference-count":74,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2017,12,14]],"date-time":"2017-12-14T00:00:00Z","timestamp":1513209600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01HD29587"],"award-info":[{"award-number":["P01HD29587"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DP1DA041722"],"award-info":[{"award-number":["DP1DA041722"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS086890"],"award-info":[{"award-number":["R01NS086890"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG057409"],"award-info":[{"award-number":["RF1AG057409"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG056259"],"award-info":[{"award-number":["R01AG056259"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology of Japan","doi-asserted-by":"crossref","award":["25350985"],"award-info":[{"award-number":["25350985"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institute of Neurological Disease and Stroke Core","award":["P30 NS076411"],"award-info":[{"award-number":["P30 NS076411"]}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>\n                    Dimethyl fumarate (DMF) is an electrophilic compound previously called BG-12 and marketed under the name Tecfidera\n                    <ns4:sup>\u00ae<\/ns4:sup>\n                    . 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\n                    <ns4:italic>Rosmarinus officinalis<\/ns4:italic>\n                    , 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.\n                  <\/ns4:p>","DOI":"10.12688\/f1000research.12111.1","type":"journal-article","created":{"date-parts":[[2017,12,14]],"date-time":"2017-12-14T09:56:13Z","timestamp":1513245373000},"page":"2138","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":94,"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"],"prefix":"10.12688","volume":"6","author":[{"given":"Takumi","family":"Satoh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3490-1259","authenticated-orcid":false,"given":"Stuart","family":"Lipton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2017,12,14]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"689-95","DOI":"10.1126\/science.7901908","article-title":"Oxidative stress, glutamate, and neurodegenerative disorders.","volume":"262","author":"J Coyle","year":"1993","journal-title":"Science."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"37-45","DOI":"10.1016\/j.tins.2006.11.004","article-title":"Redox regulation of neuronal survival mediated by electrophilic compounds.","volume":"30","author":"T Satoh","year":"2007","journal-title":"Trends 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.13106.r28103, Taixing Cui, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, USA, 14 Dec 2017, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/6-2138\/v1#referee-response-28103","order":0,"name":"referee-response-28103","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.13106.r28104, Lu Cai, Xinyue Hu, Department of Pediatrics, Pediatric Research Institute, Wendy L. Novak Diabetes Care Center, University of Louisville, Louisville, USA, 14 Dec 2017, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/6-2138\/v1#referee-response-28104","order":1,"name":"referee-response-28104","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The work was also supported by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (25350985 to TS). Additional support was provided by National Institutes of Health grants P01 HD29587, DP1 DA041722, R01 NS086890, RF1 AG 057409, R01 AG056259, and National Institute of Neurological Disease and Stroke Core grant P30 NS076411 (to SAL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":2,"name":"grant-information","label":"Grant Information"},{"value":"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.","order":0,"name":"copyright-info","label":"Copyright"}]}}