Protein / target
Kelch-like ECH-associated protein 1
Protein at a glance
Biological role
Ubiquitin-like ligase-substrate adaptor activity
Strongest disease association
multiple sclerosis
Therapeutic maturity
Clinically validated target
Druggability
Small molecule
Clinical development
3 approved · 1 in clinical development
Research activity
Emerging research
Derived from structured UniProt, Open Targets and literature data on this page.
Protein profile
Canonical identity and biological annotation from UniProt.
Function
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination (PubMed:14585973, PubMed:15379550, PubMed:15572695, PubMed:15601839, PubMed:15983046, PubMed:37339955). KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes (PubMed:15601839, PubMed:16006525). In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:16006525, PubMed:17127771, PubMed:18251510, PubMed:19489739, PubMed:29590092). In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2 (PubMed:20452972). The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation (PubMed:28380357). The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome (PubMed:15379550, PubMed:17046835)
Subcellular location
Domains and Gene Ontology detail (23)Hide
Domains & features
Gene Ontology
- Cactin filament
- CCul3-RING ubiquitin ligase complex
- Ccytoplasm
- Ccytosol
- Cendoplasmic reticulum
- Cinclusion body
- Cmidbody
- Cnucleoplasm
- Fdisordered domain specific binding
- Fidentical protein binding
- FRNA polymerase II-specific DNA-binding transcription factor binding
- Ftranscription regulator inhibitor activity
Biological roles
What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.
View supporting evidenceHide supporting evidence
Transcriptional regulation
- ·Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that reg…
- ·RNA polymerase II-specific DNA-binding transcription factor binding
- ·transcription regulator inhibitor activity
- ·negative regulation of transcription by RNA polymerase II
Immune signalling
- ·Antigen processing: Ubiquitination & Proteasome degradation
Proteolysis
- ·Ub-specific processing proteases
Muscle contraction
- ·actin filament
View underlying pathways (6)Hide underlying pathways
Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.
Interaction neighbourhood
Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.
Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.
Drugs targeting this protein
Whether each drug engages this protein directly or through a complex, and how many other targets are recorded for it. Direct binders with few recorded targets are listed first.
Kelch-like ECH-associated protein 1 inhibitor
Appears in clinical studies involving multiple sclerosis, psoriasis, relapsing-remitting multiple sclerosis, immune system disorder
ChEMBL mechanism, action type and target identity. Open Targets clinical status and indications.
Translational evidence
Why this target matters therapeutically — disease associations, drugs in development, tractability and safety, from Open Targets.
Strongest genetic associations
Human genetic evidence — the most direct causal link between this target and a disease.
Highest-confidence therapeutic associations
Diseases where a drug acting on this target has already reached clinical development.
Highest overall evidence
Remaining associations by Open Targets' aggregated evidence score.
Show all associationsHide all associations
Open Targets ranks 1,010 associations for this target and we store the top 10 by aggregated score. The long tail is largely literature co-mention and RNA-expression evidence, not evidence that this target drives those diseases.
Known drugs · 4 total
multiple sclerosis · psoriasis · relapsing-remitting multiple sclerosis
multiple sclerosis · relapsing-remitting multiple sclerosis · immune system disorder
multiple sclerosis · B-cell non-Hodgkin lymphoma · relapsing-remitting multiple sclerosis
mixed connective tissue disease · pulmonary arterial hypertension · pulmonary hypertension
Tractability
Clinical trials
Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein.
Show remaining trials (24)Hide
ClinicalTrials.gov via the drug-target graph.
Research activity
Papers linked directly to this protein. This is the protein's own literature — descriptor-derived papers are kept separate below.
Most cited
Recent
Europe PMC papers linked directly to this protein.
Forefront confidence
Our own weighting of the evidence behind each disease association. Human genetics and clinical evidence count for most; literature co-mention counts for little, because two entities sharing an abstract is not evidence that one drives the other.
The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the underlying per-type scores are shown above so the calculation can be checked.
What's happening now
Recent activity around this target, drawn from one canonical event stream. Every item is reached through a drug that targets this protein, so each event is news about that drug rather than about the protein directly.
- Regulatory approval
Approval: Dimethyl fumarate Neuraxpharm (EMA)
- Regulatory approval
Approval: Dimethyl fumarate Accord (EMA)
- Regulatory approval
Approval: Dimethyl fumarate Mylan (EMA)
- Withdrawn from market
Market withdrawal: Dimethyl fumarate Mylan (EMA)
- Withdrawn from market
Market withdrawal: Dimethyl fumarate Polpharma (EMA)
- Withdrawn from market
Market withdrawal: Dimethyl fumarate Accord (EMA)
- Withdrawn from market
Market withdrawal: Dimethyl fumarate Neuraxpharm (EMA)
- Withdrawn from market
Market withdrawal: Dimethyl fumarate Teva (EMA)
- Regulatory approval
Approval: Vumerity (EMA)
- Safety communication
Drug Safety Update: Dimethyl fumarate (Tecfidera): updated advice on the risk of progressive multifocal leukoencephalopathy (PML) associated with mild lymphopenia
- Regulatory approval
Approval: Lenalidomide Mylan (EMA)
- New publicationSARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate.
Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.