Target Information
| Target General Information | Top | |||||
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| Target ID |
T88505
(Former ID: TTDNR00714)
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| Target Name |
Nuclear factor erythroid 2-related factor 2 (Nrf2)
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| Synonyms |
Nuclear factor, erythroid derived 2, like 2; NRF2; NFE2-related factor 2; NF-E2-related factor 2; HEBP1
Click to Show/Hide
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| Gene Name |
NFE2L2
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Ataxic disorder [ICD-11: 8A03] | |||||
| Function |
Important for the coordinated up-regulation of genes in response to oxidative stress and the regulation of cellular redox conditions. May be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region. Transcription activator that binds to antioxidant response (ARE) elements in the promoter regions of target genes.
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| BioChemical Class |
Basic leucine zipper bZIP
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| UniProt ID | ||||||
| Sequence |
MMDLELPPPGLPSQQDMDLIDILWRQDIDLGVSREVFDFSQRRKEYELEKQKKLEKERQE
QLQKEQEKAFFAQLQLDEETGEFLPIQPAQHIQSETSGSANYSQVAHIPKSDALYFDDCM QLLAQTFPFVDDNEVSSATFQSLVPDIPGHIESPVFIATNQAQSPETSVAQVAPVDLDGM QQDIEQVWEELLSIPELQCLNIENDKLVETTMVPSPEAKLTEVDNYHFYSSIPSMEKEVG NCSPHFLNAFEDSFSSILSTEDPNQLTVNSLNSDATVNTDFGDEFYSAFIAEPSISNSMP SPATLSHSLSELLNGPIDVSDLSLCKAFNQNHPESTAEFNDSDSGISLNTSPSVASPEHS VESSSYGDTLLGLSDSEVEELDSAPGSVKQNGPKTPVHSSGDMVQPLSPSQGQSTHVHDA QCENTPEKELPVSPGHRKTPFTKDKHSSRLEAHLTRDELRAKALHIPFPVEKIINLPVVD FNEMMSKEQFNEAQLALIRDIRRRGKNKVAAQNCRKRKLENIVELEQDLDHLKDEKEKLL KEKGENDKSLHLLKKQLSTLYLEVFSMLRDEDGKPYSPSEYSLQQTRDGNVFLVPKSKKP DVKKN Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T22OPB | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Omaveloxolone | Drug Info | Approved | Friedreich's ataxia | [2] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | ABT-RTA-408 | Drug Info | Phase 2 | Non-small-cell lung cancer | [6] | |
| 2 | OT-551 | Drug Info | Phase 2 | Ocular inflammation | [7] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Activator | [+] 28 Activator drugs | + | ||||
| 1 | Omaveloxolone | Drug Info | [11] | |||
| 2 | 2-hydroxybenzamide derivative 1 | Drug Info | [13] | |||
| 3 | Chalcone derivative 2 | Drug Info | [13] | |||
| 4 | Chalcone derivative 3 | Drug Info | [13] | |||
| 5 | Chalcone derivative 4 | Drug Info | [13] | |||
| 6 | Diterpenoid derivative 1 | Drug Info | [13] | |||
| 7 | Diterpenoid derivative 2 | Drug Info | [13] | |||
| 8 | PMID28454500-Compound-11 | Drug Info | [13] | |||
| 9 | PMID28454500-Compound-12 | Drug Info | [13] | |||
| 10 | PMID28454500-Compound-13 | Drug Info | [13] | |||
| 11 | PMID28454500-Compound-3 | Drug Info | [13] | |||
| 12 | PMID28454500-Compound-32 | Drug Info | [13] | |||
| 13 | PMID28454500-Compound-33 | Drug Info | [13] | |||
| 14 | PMID28454500-Compound-34 | Drug Info | [13] | |||
| 15 | PMID28454500-Compound-35 | Drug Info | [13] | |||
| 16 | PMID28454500-Compound-36 | Drug Info | [13] | |||
| 17 | PMID28454500-Compound-37 | Drug Info | [13] | |||
| 18 | PMID28454500-Compound-40 | Drug Info | [13] | |||
| 19 | PMID28454500-Compound-41 | Drug Info | [13] | |||
| 20 | PMID28454500-Compound-49 | Drug Info | [13] | |||
| 21 | PMID28454500-Compound-50 | Drug Info | [13] | |||
| 22 | PMID28454500-Compound-8 | Drug Info | [13] | |||
| 23 | PMID28454500-Compound-9 | Drug Info | [13] | |||
| 24 | Pyrazino[2,1-a]isoquinolin derivative 1 | Drug Info | [13] | |||
| 25 | Pyrazino[2,1-a]isoquinolin derivative 2 | Drug Info | [13] | |||
| 26 | Pyrazino[2,1-a]isoquinolin derivative 4 | Drug Info | [13] | |||
| 27 | Pyridyl compound 1 | Drug Info | [13] | |||
| 28 | Vinyl sulfone derivative 1 | Drug Info | [13] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | ABT-RTA-408 | Drug Info | [1] | |||
| Inhibitor | [+] 30 Inhibitor drugs | + | ||||
| 1 | OT-551 | Drug Info | [12] | |||
| 2 | 1-phenyl-1,3,4-triazole derivative 1 | Drug Info | [13] | |||
| 3 | 1-phenyl-1,3,4-triazole derivative 2 | Drug Info | [13] | |||
| 4 | 1-phenyl-1,3,4-triazole derivative 3 | Drug Info | [13] | |||
| 5 | 3-phenyl propanoic derivative 1 | Drug Info | [13] | |||
| 6 | 3-phenyl propanoic derivative 2 | Drug Info | [13] | |||
| 7 | 3-phenyl propanoic derivative 3 | Drug Info | [13] | |||
| 8 | 4-(2-cyclohexylethoxy) aniline derivative 1 | Drug Info | [13] | |||
| 9 | 4-(2-cyclohexylethoxy) aniline derivative 2 | Drug Info | [13] | |||
| 10 | 4-(2-cyclohexylethoxy) aniline derivative 3 | Drug Info | [13] | |||
| 11 | 4-(2-cyclohexylethoxy) aniline derivative 4 | Drug Info | [13] | |||
| 12 | Benzamide derivative 5 | Drug Info | [13] | |||
| 13 | Benzamide derivative 6 | Drug Info | [13] | |||
| 14 | Benzo[d]oxazole derivative 1 | Drug Info | [13] | |||
| 15 | Benzo[d]oxazole derivative 2 | Drug Info | [13] | |||
| 16 | Benzo[d]oxazole derivative 3 | Drug Info | [13] | |||
| 17 | Benzo[d]oxazole derivative 4 | Drug Info | [13] | |||
| 18 | Naphthalene derivative 1 | Drug Info | [13] | |||
| 19 | PMID28454500-Compound-57 | Drug Info | [13] | |||
| 20 | PMID28454500-Compound-58 | Drug Info | [13] | |||
| 21 | PMID28454500-Compound-59 | Drug Info | [13] | |||
| 22 | PMID28454500-Compound-60 | Drug Info | [13] | |||
| 23 | PMID28454500-Compound-91 | Drug Info | [13] | |||
| 24 | PMID28454500-Compound-92 | Drug Info | [13] | |||
| 25 | PMID28454500-Compound-93 | Drug Info | [13] | |||
| 26 | PMID28454500-Compound-94 | Drug Info | [13] | |||
| 27 | PMID28454500-Compound-95 | Drug Info | [13] | |||
| 28 | PMID28454500-Compound-96 | Drug Info | [13] | |||
| 29 | Thiazole derivative 2 | Drug Info | [13] | |||
| 30 | Thiazole derivative 3 | Drug Info | [13] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Protein processing in endoplasmic reticulum | hsa04141 | Affiliated Target |
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| Class: Genetic Information Processing => Folding, sorting and degradation | Pathway Hierarchy | ||
| Degree | 11 | Degree centrality | 1.18E-03 | Betweenness centrality | 9.46E-04 |
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| Closeness centrality | 2.23E-01 | Radiality | 1.39E+01 | Clustering coefficient | 9.09E-02 |
| Neighborhood connectivity | 2.36E+01 | Topological coefficient | 1.12E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Protein processing in endoplasmic reticulum | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL5 Signaling Pathway | |||||
| WikiPathways | [+] 9 WikiPathways | + | ||||
| 1 | Oxidative Stress | |||||
| 2 | Transcriptional activation by NRF2 | |||||
| 3 | NRF2 pathway | |||||
| 4 | Nuclear Receptors Meta-Pathway | |||||
| 5 | Aryl Hydrocarbon Receptor Pathway | |||||
| 6 | Mesodermal Commitment Pathway | |||||
| 7 | Aryl Hydrocarbon Receptor | |||||
| 8 | Quercetin and Nf-kB/ AP-1 Induced Cell Apoptosis | |||||
| 9 | Arylhydrocarbon receptor (AhR) signaling pathway | |||||
| References | Top | |||||
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| REF 1 | National Cancer Institute Drug Dictionary (drug id 756624). | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 216718. | |||||
| REF 3 | ClinicalTrials.gov (NCT02970682) SFX-01 in the Treatment and Evaluation of Metastatic Breast Cancer (STEM). U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT00306488) OT-551 Antioxidant Eye Drops to Treat Geographic Atrophy in Age-Related Macular Degeneration. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT04053543) CXA-10 Study in Subjects With Pulmonary Arterial Hypertension. U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT02142959) RTA 408 Lotion in Patients at Risk for Radiation Dermatitis - PRIMROSE. U.S. National Institutes of Health. | |||||
| REF 7 | ClinicalTrials.gov (NCT00306488) OT-551 Antioxidant Eye Drops to Treat Geographic Atrophy in Age-Related Macular Degeneration. U.S. National Institutes of Health. | |||||
| REF 8 | Clinical pipeline report, company report or official report of vTv Therapeutics. | |||||
| REF 9 | The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. Eur J Pharmacol. 2017 May 5;802:76-84. | |||||
| REF 10 | Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019 Apr;18(4):295-317. | |||||
| REF 11 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 12 | New hope for dry AMD. Nat Rev Drug Discov. 2013 Jul;12(7):501-2. | |||||
| REF 13 | Recent progress in the development of small molecule Nrf2 modulators: a patent review (2012-2016).Expert Opin Ther Pat. 2017 Jul;27(7):763-785. | |||||
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