PMID- 29263788
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 2046-1402 (Print)
IS  - 2046-1402 (Electronic)
IS  - 2046-1402 (Linking)
VI  - 6
DP  - 2017
TI  - 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.
PG  - 2138
LID - 10.12688/f1000research.12111.1 [doi]
LID - 2138
AB  - Dimethyl fumarate (DMF) is an electrophilic compound previously called BG-12 and 
      marketed under the name Tecfidera ((R)). 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.
FAU - Satoh, Takumi
AU  - Satoh T
AD  - Department of Anti-Aging Food Research, School of Bioscience and Biotechnology, 
      Tokyo University of Technology, Tokyo, Japan.
FAU - Lipton, Stuart
AU  - Lipton S
AUID- ORCID: 0000-0002-3490-1259
AD  - Neuroscience Translational Center and Department of Molecular Medicine, The 
      Scripps Research Institute, La Jolla, CA, USA.
AD  - Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, USA.
AD  - Department of Neurosciences, University of California, School of Medicine, La 
      Jolla, CA, USA.
LA  - eng
GR  - P30 NS076411/NS/NINDS NIH HHS/United States
GR  - R01 AG056259/AG/NIA NIH HHS/United States
GR  - RF1 AG057409/AG/NIA NIH HHS/United States
GR  - R01 NS086890/NS/NINDS NIH HHS/United States
GR  - DP1 DA041722/DA/NIDA NIH HHS/United States
GR  - P01 HD029587/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Review
DEP - 20171214
PL  - England
TA  - F1000Res
JT  - F1000Research
JID - 101594320
PMC - PMC5730864
OTO - NOTNLM
OT  - Dimethyl Fumarate
OT  - Electrophilic Drugs
OT  - KEAP1
OT  - Nrf2
COIS- Competing interests: The authors disclose that their academic institutions have 
      filed patents for PED activators of NRF2 for cell protection in various 
      maladies.No competing interests were disclosed.No competing interests were 
      disclosed.No competing interests were disclosed.
EDAT- 2017/12/22 06:00
MHDA- 2017/12/22 06:01
PMCR- 2017/12/14
CRDT- 2017/12/22 06:00
PHST- 2017/11/17 00:00 [accepted]
PHST- 2017/12/22 06:00 [entrez]
PHST- 2017/12/22 06:00 [pubmed]
PHST- 2017/12/22 06:01 [medline]
PHST- 2017/12/14 00:00 [pmc-release]
AID - 10.12688/f1000research.12111.1 [doi]
PST - epublish
SO  - F1000Res. 2017 Dec 14;6:2138. doi: 10.12688/f1000research.12111.1. eCollection 
      2017.