Target Information
| Target General Information | Top | |||||
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| Target ID |
T83198
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| Target Name |
Cysteines of Keap1 (KEAP1 Cysteines)
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| Synonyms |
Kelch-like protein 19-Cysteines; Kelch-like ECH-associated protein 1-Cysteines; KLHL19-Cysteines; KIAA0132-Cysteines; INrf2-Cysteines; Cytosolic inhibitor of Nrf2-Cysteines
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| Gene Name |
KEAP1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Pulmonary hypertension [ICD-11: BB01] | |||||
| 2 | Urinary system clinical sympton [ICD-11: MF8Y] | |||||
| Function |
Retains NFE2L2/NRF2 and may also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome. Acts as a substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1 and targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression.
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| UniProt ID | ||||||
| Sequence |
MQPDPRPSGAGACCRFLPLQSQCPEGAGDAVMYASTECKAEVTPSQHGNRTFSYTLEDHT
KQAFGIMNELRLSQQLCDVTLQVKYQDAPAAQFMAHKVVLASSSPVFKAMFTNGLREQGM EVVSIEGIHPKVMERLIEFAYTASISMGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLD PSNAIGIANFAEQIGCVELHQRAREYIYMHFGEVAKQEEFFNLSHCQLVTLISRDDLNVR CESEVFHACINWVKYDCEQRRFYVQALLRAVRCHSLTPNFLQMQLQKCEILQSDSRCKDY LVKIFEELTLHKPTQVMPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSDGTWLRLADLQV PRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCAPMSVPRNRIGVGV IDGHIYAVGGSHGCIHHNSVERYEPERDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDG TNRLNSAECYYPERNEWRMITAMNTIRSGAGVCVLHNCIYAAGGYDGQDQLNSVERYDVE TETWTFVAPMKHRRSALGITVHQGRIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRMTSG RSGVGVAVTMEPCRKQIDQQNCTC Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T36YWU | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | CXA10 | Drug Info | Phase 2 | Pulmonary arterial hypertension | [2] | |
| Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
| 1 | VCB101 | Drug Info | Preclinical | Multiple sclerosis | [3] | |
| 2 | VCB102 | Drug Info | Preclinical | Psoriasis vulgaris | [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inactivator | [+] 3 Inactivator drugs | + | ||||
| 1 | CXA10 | Drug Info | [4] | |||
| 2 | VCB101 | Drug Info | [5] | |||
| 3 | VCB102 | Drug Info | [5] | |||
| Modulator | [+] 32 Modulator drugs | + | ||||
| 1 | 2-hydroxybenzamide derivative 1 | Drug Info | [1] | |||
| 2 | 2-hydroxybenzamide derivative 2 | Drug Info | [1] | |||
| 3 | Chalcone derivative 1 | Drug Info | [1] | |||
| 4 | Chalcone derivative 2 | Drug Info | [1] | |||
| 5 | Chalcone derivative 3 | Drug Info | [1] | |||
| 6 | Chalcone derivative 4 | Drug Info | [1] | |||
| 7 | Diterpenoid derivative 1 | Drug Info | [1] | |||
| 8 | Diterpenoid derivative 2 | Drug Info | [1] | |||
| 9 | PMID28454500-Compound-10 | Drug Info | [1] | |||
| 10 | PMID28454500-Compound-11 | Drug Info | [1] | |||
| 11 | PMID28454500-Compound-12 | Drug Info | [1] | |||
| 12 | PMID28454500-Compound-13 | Drug Info | [1] | |||
| 13 | PMID28454500-Compound-3 | Drug Info | [1] | |||
| 14 | PMID28454500-Compound-32 | Drug Info | [1] | |||
| 15 | PMID28454500-Compound-33 | Drug Info | [1] | |||
| 16 | PMID28454500-Compound-34 | Drug Info | [1] | |||
| 17 | PMID28454500-Compound-35 | Drug Info | [1] | |||
| 18 | PMID28454500-Compound-36 | Drug Info | [1] | |||
| 19 | PMID28454500-Compound-37 | Drug Info | [1] | |||
| 20 | PMID28454500-Compound-40 | Drug Info | [1] | |||
| 21 | PMID28454500-Compound-41 | Drug Info | [1] | |||
| 22 | PMID28454500-Compound-49 | Drug Info | [1] | |||
| 23 | PMID28454500-Compound-50 | Drug Info | [1] | |||
| 24 | PMID28454500-Compound-8 | Drug Info | [1] | |||
| 25 | PMID28454500-Compound-9 | Drug Info | [1] | |||
| 26 | Pyrazino[2,1-a]isoquinolin derivative 1 | Drug Info | [1] | |||
| 27 | Pyrazino[2,1-a]isoquinolin derivative 2 | Drug Info | [1] | |||
| 28 | Pyrazino[2,1-a]isoquinolin derivative 3 | Drug Info | [1] | |||
| 29 | Pyrazino[2,1-a]isoquinolin derivative 4 | Drug Info | [1] | |||
| 30 | Pyridyl compound 1 | Drug Info | [1] | |||
| 31 | Trepenoid derivative 1 | Drug Info | [1] | |||
| 32 | Vinyl sulfone derivative 1 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Tecfidera | Ligand Info | |||||
| Structure Description | Crystal structure of Keap1 in complex with dimethyl fumarate (DMF) | PDB:6LRZ | ||||
| Method | X-ray diffraction | Resolution | 1.54 Å | Mutation | No | [6] |
| PDB Sequence |
RGSHMVGRLI
328 YTAGGYFRQS338 LSYLEAYNPS348 NGSWLRLADL358 QVPRSGLAGC368 VVGGLLYAVG 378 GRNNSPDGNT388 DSSALDCYNP398 MTNQWSPCAS408 MSVPRNRIGV418 GVIDGHIYAV 428 GGSHGCIHHS438 SVERYEPERD448 EWHLVAPMLT458 RRIGVGVAVL468 NRLLYAVGGF 478 DGTNRLNSAE488 CYYPERNEWR498 MITPMNTIRS508 GAGVCVLHNC518 IYAAGGYDGQ 528 DQLNSVERYD538 VETETWTFVA548 PMRHHRSALG558 ITVHQGKIYV568 LGGYDGHTFL 578 DSVECYDPDS588 DTWSEVTRMT598 SGRSGVGVAV608 TMEPC
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| Ligand Name: 1-Methoxy-2-[2-(2-Methoxy-Ethoxy]-Ethane | Ligand Info | |||||
| Structure Description | Crystal structure of Keap1 in complex with dimethyl fumarate (DMF) | PDB:6LRZ | ||||
| Method | X-ray diffraction | Resolution | 1.54 Å | Mutation | No | [6] |
| PDB Sequence |
RGSHMVGRLI
328 YTAGGYFRQS338 LSYLEAYNPS348 NGSWLRLADL358 QVPRSGLAGC368 VVGGLLYAVG 378 GRNNSPDGNT388 DSSALDCYNP398 MTNQWSPCAS408 MSVPRNRIGV418 GVIDGHIYAV 428 GGSHGCIHHS438 SVERYEPERD448 EWHLVAPMLT458 RRIGVGVAVL468 NRLLYAVGGF 478 DGTNRLNSAE488 CYYPERNEWR498 MITPMNTIRS508 GAGVCVLHNC518 IYAAGGYDGQ 528 DQLNSVERYD538 VETETWTFVA548 PMRHHRSALG558 ITVHQGKIYV568 LGGYDGHTFL 578 DSVECYDPDS588 DTWSEVTRMT598 SGRSGVGVAV608 TMEPC
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| 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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There is no similarity protein (E value < 0.005) for this target
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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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| Ubiquitin mediated proteolysis | hsa04120 | Affiliated Target |
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| Class: Genetic Information Processing => Folding, sorting and degradation | Pathway Hierarchy | ||
| Degree | 16 | Degree centrality | 1.72E-03 | Betweenness centrality | 1.36E-03 |
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| Closeness centrality | 2.36E-01 | Radiality | 1.41E+01 | Clustering coefficient | 6.67E-02 |
| Neighborhood connectivity | 2.67E+01 | Topological coefficient | 7.33E-02 | Eccentricity | 12 |
| 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 | ||||||
| References | Top | |||||
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| REF 1 | 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. | |||||
| REF 2 | ClinicalTrials.gov (NCT04053543) CXA-10 Study in Subjects With Pulmonary Arterial Hypertension. U.S. National Institutes of Health. | |||||
| REF 3 | Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019 Apr;18(4):295-317. | |||||
| REF 4 | The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases. Biophys Rev. 2017 Feb;9(1):41-56. | |||||
| REF 5 | NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases. Biomolecules. 2020 Jun 14;10(6):904. | |||||
| REF 6 | Structural insights into the multiple binding modes of Dimethyl Fumarate (DMF) and its analogs to the Kelch domain of Keap1. FEBS J. 2021 Mar;288(5):1599-1613. | |||||
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