KEAP1
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Also known as KIAA0132MGC10630MGC1114MGC20887MGC4407MGC9454INrf2KLHL19
Summary
KEAP1 (kelch like ECH associated protein 1, HGNC:23177) is a protein-coding gene on chromosome 19p13.2, encoding Kelch-like ECH-associated protein 1 (Q14145). 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. In precision oncology, KEAP1 Mutation confers sensitivity to Durvalumab Regimen + Chemotherapy + Tremelimumab in Lung Non-small Cell Carcinoma (CIViC Level A); 3 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 19.4% of cell lines).
This gene encodes a cytoplasmic regulatory protein that plays a role in the cellular response to oxidative and electrophilic stress. The encoded protein regulates NRF2, a transcription factor that controls the expression of antioxidant and cytoprotective genes. Under non-stress conditions, KEAP1 binds NRF2 and promotes its ubiquitination and proteasomal degradation, thereby maintaining low NRF2 levels. During oxidative or electrophilic stress, conformational changes in KEAP1 impair its ability to promote NRF2 degradation, allowing NRF2 to activate genes that protect cells from oxidative damage and toxic insults.
Source: NCBI Gene 9817 — RefSeq curated summary.
At a glance
- Gene–disease (curated): goiter, multinodular 1, with or without Sertoli-Leydig cell tumors (Supportive, GenCC)
- GWAS associations: 6
- Clinical variants (ClinVar): 80 total
- Phenotypes (HPO): 14
- Druggable target: yes — 9 molecules with ChEMBL bioactivity
- Precision-oncology evidence (CIViC): 4 curated variant–drug associations
- Cancer driver (intOGen): activating (oncogene-like) across 6 cancer types
- Cancer dependency (DepMap): dependent in 19.4% of screened cell lines
- MANE Select transcript:
NM_203500
Identifiers
Gene identifiers
| Field | Value |
|---|---|
| HGNC ID | HGNC:23177 |
| Approved symbol | KEAP1 |
| Name | kelch like ECH associated protein 1 |
| Location | 19p13.2 |
| Locus type | gene with protein product |
| Status | Approved |
| Aliases | KIAA0132, MGC10630, MGC1114, MGC20887, MGC4407, MGC9454, INrf2, KLHL19 |
| Ensembl gene | ENSG00000079999 |
| Ensembl biotype | protein_coding |
| OMIM | 606016 |
| Entrez | 9817 |
Gene structure
Transcript identifiers
Ensembl transcripts: 19 — 15 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron
ENST00000171111, ENST00000393623, ENST00000585845, ENST00000588024, ENST00000590237, ENST00000590593, ENST00000591039, ENST00000591419, ENST00000592055, ENST00000592478, ENST00000910164, ENST00000910165, ENST00000910166, ENST00000910167, ENST00000953683, ENST00000953684, ENST00000953685, ENST00000953686, ENST00000953687
RefSeq mRNA: 2 — MANE Select: NM_203500
NM_012289, NM_203500
CCDS: CCDS12239
Canonical transcript exons
ENST00000171111 — 6 exons
| Exon | Start | End |
|---|---|---|
| ENSE00000679299 | 10489648 | 10489853 |
| ENSE00001217262 | 10491577 | 10492262 |
| ENSE00002737191 | 10503241 | 10503356 |
| ENSE00002867049 | 10486125 | 10486818 |
| ENSE00003678645 | 10489192 | 10489368 |
| ENSE00003799100 | 10499395 | 10500080 |
Expression profiles
Bgee: expression breadth ubiquitous, 294 present calls, max score 97.75.
FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.5754 / max 140.1177, expressed in 1798 samples.
FANTOM5 promoters (4 alternative TSS)
| Promoter ID | TPM avg | Samples expressed |
|---|---|---|
| 179144 | 7.0990 | 1707 |
| 179142 | 3.2978 | 1649 |
| 179143 | 3.0971 | 1593 |
| 179145 | 0.0816 | 32 |
Top tissues by expression
300 total, by Bgee expression score (0-100, higher = more expressed):
| Tissue | Anatomy ID | Expression score | Quality |
|---|---|---|---|
| hindlimb stylopod muscle | UBERON:0004252 | 97.75 | gold quality |
| gastrocnemius | UBERON:0001388 | 97.45 | gold quality |
| muscle of leg | UBERON:0001383 | 97.02 | gold quality |
| apex of heart | UBERON:0002098 | 96.82 | gold quality |
| muscle organ | UBERON:0001630 | 96.50 | gold quality |
| skeletal muscle organ | UBERON:0014892 | 96.50 | gold quality |
| stromal cell of endometrium | CL:0002255 | 95.92 | gold quality |
| skeletal muscle tissue of rectus abdominis | UBERON:0004511 | 95.92 | gold quality |
| lower esophagus mucosa | UBERON:0035834 | 95.68 | gold quality |
| skeletal muscle tissue | UBERON:0001134 | 95.60 | gold quality |
| quadriceps femoris | UBERON:0001377 | 95.11 | gold quality |
| vastus lateralis | UBERON:0001379 | 95.06 | gold quality |
| C1 segment of cervical spinal cord | UBERON:0006469 | 94.70 | gold quality |
| gluteal muscle | UBERON:0002000 | 94.55 | gold quality |
| skeletal muscle tissue of biceps brachii | UBERON:0004502 | 94.41 | gold quality |
| mucosa of transverse colon | UBERON:0004991 | 94.17 | gold quality |
| right lobe of liver | UBERON:0001114 | 94.08 | gold quality |
| esophagus mucosa | UBERON:0002469 | 94.01 | gold quality |
| spinal cord | UBERON:0002240 | 94.00 | gold quality |
| prefrontal cortex | UBERON:0000451 | 93.98 | gold quality |
| muscle tissue | UBERON:0002385 | 93.97 | gold quality |
| triceps brachii | UBERON:0001509 | 93.94 | gold quality |
| body of tongue | UBERON:0011876 | 93.88 | gold quality |
| heart left ventricle | UBERON:0002084 | 93.76 | gold quality |
| ventricular zone | UBERON:0003053 | 93.73 | gold quality |
| ganglionic eminence | UBERON:0004023 | 93.73 | gold quality |
| deltoid | UBERON:0001476 | 93.68 | gold quality |
| olfactory segment of nasal mucosa | UBERON:0005386 | 93.68 | gold quality |
| cardiac ventricle | UBERON:0002082 | 93.53 | gold quality |
| esophagus | UBERON:0001043 | 93.50 | gold quality |
Single-cell (SCXA)
Detected in 1 experiment(s), a significant marker in 1.
| Experiment | Marker? | Max mean expression |
|---|---|---|
| E-ANND-3 | yes | 11.12 |
Regulation
Is transcription factor: no
Upstream regulators (CollecTRI, top): DNMT3A, DNMT3B, NFE2L2, NFKB, RELA, SP1, SPI1, TET1, TP53
miRNA regulators (miRDB)
30 targeting KEAP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):
| miRNA | Max score | Avg score | miRNA target_count |
|---|---|---|---|
| HSA-MIR-4481 | 100.00 | 66.42 | 1669 |
| HSA-MIR-3065-5P | 99.97 | 71.56 | 3281 |
| HSA-LET-7C-3P | 99.95 | 73.42 | 2862 |
| HSA-MIR-141-3P | 99.94 | 72.79 | 2421 |
| HSA-MIR-200A-3P | 99.94 | 72.68 | 2420 |
| HSA-MIR-627-3P | 99.90 | 71.42 | 3316 |
| HSA-MIR-7159-5P | 99.53 | 72.12 | 2472 |
| HSA-MIR-10399-5P | 99.17 | 69.87 | 2610 |
| HSA-MIR-6504-3P | 99.17 | 69.31 | 2891 |
| HSA-MIR-4292 | 99.16 | 65.57 | 1767 |
| HSA-MIR-6791-5P | 99.16 | 65.92 | 1844 |
| HSA-MIR-6815-3P | 99.13 | 68.98 | 1530 |
| HSA-MIR-3117-5P | 99.04 | 67.93 | 618 |
| HSA-MIR-7151-3P | 99.04 | 69.72 | 2370 |
| HSA-MIR-6876-3P | 98.97 | 65.69 | 765 |
| HSA-MIR-626 | 98.89 | 66.21 | 762 |
| HSA-MIR-26B-3P | 98.71 | 67.49 | 1102 |
| HSA-MIR-423-5P | 98.69 | 67.48 | 1522 |
| HSA-MIR-3184-5P | 98.56 | 67.13 | 1491 |
| HSA-MIR-4726-3P | 98.49 | 63.89 | 1385 |
| HSA-MIR-1292-5P | 96.74 | 62.14 | 238 |
| HSA-MIR-4529-3P | 96.40 | 66.46 | 582 |
| HSA-MIR-6823-5P | 96.26 | 65.69 | 919 |
| HSA-MIR-4471 | 95.11 | 66.84 | 755 |
| HSA-MIR-8059 | 95.11 | 66.30 | 646 |
| HSA-MIR-5009-5P | 94.82 | 63.89 | 775 |
| HSA-MIR-8058 | 94.76 | 63.41 | 632 |
| HSA-MIR-1269A | 92.75 | 64.61 | 542 |
| HSA-MIR-1269B | 92.75 | 64.73 | 538 |
| HSA-MIR-4449 | 88.89 | 64.59 | 48 |
Functional genomics
DepMap (CRISPR cell-line fitness): dependent in 19.4% of screened cell lines.
Literature-anchored findings (GeneRIF, showing 40)
- In epithelial cells derived from retina and inner ear, Keap1 is a component of focal adhesions and zipper junctions. (PMID:11921171)
- Keap1 dimerization causes Nrf2 sequestration (PMID:12145307)
- phosphorylation of serine 40 is necessary for nuclear factor((erythroid-derived 2)like 2(Nrf2) release from Inhibitor of Nrf2(INrf2) (PMID:12947090)
- Data show that Keap1 associates with the N-terminal region of Cullin 3 through the IVR domain and promotes the ubiquitination of Nrf2 in cooperation with the Cullin 3-Roc1 complex. (PMID:15282312)
- hKeap1 regulates fetal Alz-50 reactive clone 1 in addition to its known role in control of Nrf2 (PMID:15379550)
- structure of the Kelch domain of Keap1 protein represents a high quality model for the superfamily of eukaryotic kelch repeat proteins (PMID:15475350)
- KEAP1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. (PMID:15572695)
- crystallographic analysis of the Kelch domain from human Keap1 (PMID:15583386)
- Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination by the CUL3-ROC1 ligase and subsequent degradation by the proteasome (PMID:15601839)
- A downstream product of COX-2, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), activated the Nrf2 regulatory pathway in HAECs through binding to the cysteines of Keap1 (PMID:15917255)
- Keap1 is a BTB-Kelch substrate adaptor protein for Cul3, which targets it for degradation by a proteasome-independent pathway (PMID:15983046)
- stabilization of Nrf2 in cells under stress represents the central regulatory response mediated by mechanisms that interfere with its interaction with Keap1, leading to the induction of antioxidant enzymes important to maintain cellular redox homeostasis (PMID:16000310)
- Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. (PMID:16006525)
- These findings suggest a role for FAC1 in apoptosis following release of Nrf2 from Keap1 in response to oxidative stress. (PMID:16137655)
- x-ray crystallographic analysis of solvent and side-chain interactions in the Kelch domain of Keap1 (PMID:16204884)
- Somatic mutation and a gene variation in human lung cancer cells change glycine to cysteine in the KEAP1 DGR domain, introducing local conformational changes that reduce Keap1’s affinity for Nrf2. (PMID:16507366)
- A recombinant protein containing both the Kelch/DGR domain and the C-terminal region of mouse Keap1 was expressed in Escherichia coli, purified to near-homogeneity and crystallized by the sitting-drop vapour-diffusion method. (PMID:16508120)
- Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents (PMID:17020408)
- The N terminus of the PGAM5 protein contains a conserved NXESGE motif that binds to the substrate binding pocket in the Kelch domain of Keap1. (PMID:17046835)
- review will discuss recent progress in the field of the Nrf2-Keap1 signaling pathway, with emphasis on the mechanistic studies of Nrf2 regulation by Keap1–{REVIEW} (PMID:17145701)
- Nrf2-Keap1-dependent UGT1A1 induction by prooxidants might represent a key adaptive response to cellular oxidative stress (PMID:17259171)
- In 84 Japanese type 2 diabetes subjects, 18 genetic variations were detected in the KEAP1 gene, including 13 novel ones. (PMID:17603223)
- KEAP1 controls postinduction repression of the NRF2-mediated antioxidant response by escorting nuclear export of NRF2. (PMID:17636022)
- Importantly, our findings suggest that a paradox exists whereby Nrf2 activity is beneficial in non-malignant cells but in cancer cells it may provide a selective advantage for clonal expansion. (PMID:17822677)
- endogenous Keap1 remains mostly in the cytoplasm, and electrophiles promote nuclear accumulation of Nrf2 without altering the subcellular localization of Keap1 (PMID:17903176)
- Nrf2 regulates INrf2 by controlling its transcription, and INrf2 controls Nrf2 by degrading it. (PMID:17925401)
- C151 is the most important site of alkylation on Keap1 by chemoprevention agents that function by activating the antioxidant response element through Nrf2. (PMID:17980616)
- in response to CSNO Keap1 accumulates in the nucleus with a time course similar to that of Nrf2. (PMID:18062931)
- ProTalpha and Nrf2 compete for interaction with Keap1, therefore ProTalpha is able to liberate Nrf2 from complex with Keap1 and hence contribute to Nrf2-dependent transcription. (PMID:18240569)
- Cys151 adduction confers a critical alkylation sensor function upon Keap1 (PMID:18251510)
- Keap1 prevents activation of Nrf2 and lung cancer cell growth (PMID:18316592)
- ap1-dependent signaling pathway for the induction of the constitutive GST A1 expression during epithelial cell differentiati in Caco-2 cells. (PMID:18476723)
- Keap1 expression is regulated by an epigenetic mechanism in lung cancer. (PMID:18555005)
- Aberrant Nrf2 activation provoked by Keap1 alteration is one of the molecular mechanisms for chemotherapeutic resistance in gallbladder cancer (PMID:18692501)
- provides in vivo validation of the two-site substrate recognition model for Nrf2 activation by the Keap1-Cul3-based E3 ligase (PMID:18757741)
- Targeting Nrf2 activity in lung cancers, particularly those with Keap1 mutations, could be a promising strategy to inhibit tumor growth and circumvent chemoresistance. (PMID:18829555)
- KEAP1 mutations; activation of an adaptive response in cancer (Review) (PMID:19321346)
- In renal cell carcinoma, Keap1 is associated with a more advanced disease, a higher grade and a poorer prognosis. (PMID:19424632)
- Modification of Cys(151) of human Keap1, by mutation to a tryptophan, relieves the repression by Keap1 and allows activation of the antioxidant response element by Nrf2. (PMID:19489739)
- Activating Nrf2 pathways in tissue-specific Keap1 knockout mice and human epithelial cells represents an important genetic approach against oxidant-induced lung damage. (PMID:19520915)
Cross-species orthologs
3 orthologs
| Organism | Symbol | Gene ID |
|---|---|---|
| danio_rerio | keap1b | ENSDARG00000074634 |
| mus_musculus | Keap1 | ENSMUSG00000003308 |
| rattus_norvegicus | Keap1 | ENSRNOG00000020878 |
Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359), KLHL33 (ENSG00000185271)
Protein
Protein identifiers
Kelch-like ECH-associated protein 1 — Q14145 (reviewed: Q14145)
Alternative names: Cytosolic inhibitor of Nrf2, Kelch-like protein 19
All UniProt accessions (7): Q14145, K7EJ49, K7EJD8, K7EMY1, K7EPZ3, K7EQX2, K7ESE0
UniProt curated annotations — full annotation on 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. 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. 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. 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. The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation. The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome.
Subunit / interactions. Component of the BCR(KEAP1) E3 ubiquitin ligase complex, at least composed of 2 molecules of CUL3, 2 molecules of KEAP1, and RBX1. Interacts with NFE2L2/NRF2; the interaction is direct. Forms a ternary complex with NFE2L2/NRF2 and PGAM5. Interacts with (phosphorylated) SQSTM1/p62; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering it in inclusion bodies, promoting its degradation. Interacts with NFE2L1. Interacts with BPTF and PTMA. Interacts with MAP1LC3B. Interacts indirectly with ENC1. Interacts with SESN1 and SESN2. Interacts with HSP90AA1 and HSP90AB1. Interacts with PGCKA1; this interaction prevents the ubiquitination of KEAP1 by TRIM25, thus protecting KEAP1 from degradation. (Microbial infection) Interacts with ebolavirus protein VP24; this interaction activates transcription factor NFE2L2/NRF2 by blocking its interaction with KEAP1.
Subcellular location. Cytoplasm. Nucleus.
Tissue specificity. Broadly expressed, with highest levels in skeletal muscle.
Post-translational modifications. Non-enzymatic covalent modifications of reactive cysteines by electrophile metabolites inactivate the BCR(KEAP1) complex. Accumulation of fumarate promotes the formation of cysteine S-succination (S-(2-succinyl)cysteine), leading to inactivate the BCR(KEAP1) complex and promote NFE2L2/NRF2 nuclear accumulation and activation. Nitric oxide-dependent 8-Nitro-cGMP formation promotes cysteine guanylation (S-cGMP-cysteine), leading to NFE2L2/NRF2 nuclear accumulation and activation. Itaconate, an anti-inflammatory metabolite generated in response to lipopolysaccharide, alkylates cysteines, activating NFE2L2/NRF2. Methylglyoxal, a reactive metabolite that accumulates when the glycolytic enzyme PGK1 is inhibited, promotes formation of a methylimidazole cross-link between proximal Cys-151 and Arg-135 on another KEAP1 molecule, resulting in an inactive dimer that inactivates the BCR(KEAP1) complex. Degraded via a proteasomal-independent process during selective autophagy: interaction with phosphorylated SQSTM1/p62 sequesters KEAP1 in inclusion bodies, leading to its degradation. Auto-ubiquitinated by the BCR(KEAP1) complex. Quinone-induced oxidative stress, but not sulforaphane, increases its ubiquitination. Ubiquitination and subsequent degradation is most pronounced following prolonged exposure of cells to oxidative stress, particularly in glutathione-deficient cells that are highly susceptible to oxidative stress. Deubiquitinated by USP25; leading to stabilization. Ubiquitinated by TRIM25; leading to degradation upon ER stress.
Activity regulation. Ubiquitin ligase activity of the BCR(KEAP1) complex is inhibited by oxidative stress and electrophile metabolites such as sulforaphane. Electrophile metabolites react with reactive cysteine residues in KEAP1 and trigger non-enzymatic covalent modifications of these cysteine residues, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex. Selective autophagy also inactivates the BCR(KEAP1) complex via interaction between KEAP1 and SQSTM1/p62, which sequesters the complex in inclusion bodies and promotes its degradation.
Domain organisation. KEAP1 contains reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules, which react with sulfhydryl groups and modify the cysteine sensors, leading to impair ability of the BCR(KEAP1) complex to ubiquitinate target proteins. The Kelch repeats mediate interaction with NFE2L2/NRF2, BPTF and PGAM5.
Pathway. Protein modification; protein ubiquitination.
Similarity. Belongs to the KEAP1 family.
RefSeq proteins (2): NP_036421, NP_987096* (*=MANE)
Domains & families (InterPro)
| ID | Name | Type |
|---|---|---|
| IPR000210 | BTB/POZ_dom | Domain |
| IPR006652 | Kelch_1 | Repeat |
| IPR011333 | SKP1/BTB/POZ_sf | Homologous_superfamily |
| IPR011705 | BACK | Domain |
| IPR015915 | Kelch-typ_b-propeller | Homologous_superfamily |
| IPR017096 | BTB-kelch_protein | Family |
| IPR030563 | KEAP1_BTB_POZ_dom | Domain |
| IPR047098 | KEAP1_BACK | Domain |
Pfam: PF00651, PF01344, PF07707, PF24681
UniProt features (116 total): strand 39, mutagenesis site 22, modified residue 12, sequence variant 10, helix 9, turn 7, repeat 6, site 5, domain 2, cross-link 2, chain 1, sequence conflict 1
Structure
Experimental structures (PDB)
122 structures, top 30 by resolution.
| PDB | Method | Resolution (Å) |
|---|---|---|
| 8XGK | X-RAY DIFFRACTION | 1.32 |
| 1ZGK | X-RAY DIFFRACTION | 1.35 |
| 8XGV | X-RAY DIFFRACTION | 1.42 |
| 6TYM | X-RAY DIFFRACTION | 1.42 |
| 9KVW | X-RAY DIFFRACTION | 1.44 |
| 8IXS | X-RAY DIFFRACTION | 1.48 |
| 2FLU | X-RAY DIFFRACTION | 1.5 |
| 8IVR | X-RAY DIFFRACTION | 1.5 |
| 9R1Z | X-RAY DIFFRACTION | 1.5 |
| 8PKW | X-RAY DIFFRACTION | 1.54 |
| 6LRZ | X-RAY DIFFRACTION | 1.54 |
| 8PKV | X-RAY DIFFRACTION | 1.55 |
| 9M24 | X-RAY DIFFRACTION | 1.57 |
| 6V6Z | X-RAY DIFFRACTION | 1.6 |
| 9R1C | X-RAY DIFFRACTION | 1.69 |
| 9VD2 | X-RAY DIFFRACTION | 1.7 |
| 9IH9 | X-RAY DIFFRACTION | 1.7 |
| 8PKU | X-RAY DIFFRACTION | 1.73 |
| 6HWS | X-RAY DIFFRACTION | 1.75 |
| 8PKX | X-RAY DIFFRACTION | 1.79 |
| 4IFJ | X-RAY DIFFRACTION | 1.8 |
| 4IFL | X-RAY DIFFRACTION | 1.8 |
| 8IVG | X-RAY DIFFRACTION | 1.8 |
| 9PHR | X-RAY DIFFRACTION | 1.8 |
| 7EXI | X-RAY DIFFRACTION | 1.82 |
| 1U6D | X-RAY DIFFRACTION | 1.85 |
| 5F72 | X-RAY DIFFRACTION | 1.85 |
| 9DU7 | X-RAY DIFFRACTION | 1.87 |
| 9ETY | X-RAY DIFFRACTION | 1.87 |
| 7K2A | X-RAY DIFFRACTION | 1.9 |
Predicted structure (AlphaFold)
| Model | pLDDT | Fraction very-high |
|---|---|---|
| AF-Q14145-F1 | 90.44 | 0.83 |
Antibody-complex structures (SAbDab): 1 — 5F72
Functional residue map
Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.
Catalytic / active sites (5): 257 (sensor for electrophilic agents); 273 (sensor for electrophilic agents); 288 (sensor for electrophilic agents); 434 (sensor for electrophilic agents); 151 (sensor for electrophilic agents)
Post-translational modifications (14): 38, 151, 151, 151, 241, 257, 273, 288, 288, 319, 434, 613, 135, 151
Mutagenesis-validated functional residues (22):
| Position | Phenotype |
|---|---|
| 15 | reduced formation of a high-molecular mass keap1 molecule when methylglyoxal accumulates. |
| 123–127 | abolished interaction with nfe2l2/nrf2; when associated with 161-a-a-162. |
| 125–127 | increases ubiquitination and proteolytic degradation. |
| 135 | reduced formation of a high-molecular mass keap1 molecule when methylglyoxal accumulates. |
| 151 | substitution with a small side chain that prevents covalent modification by an electrophile; promotes constitutive ubiqu |
| 151 | substitution with a bulky side chain that mimicks covalent modification by an electrophile; prevents ubiquitination and |
| 161–162 | abolished interaction with nfe2l2/nrf2; when associated with 123-a–a-127. |
| 162–164 | increases ubiquitination and proteolytic degradation. |
| 273 | abolishes repression of nfe2l2/nrf2-dependent gene expression. slows down degradation of nfe2l2/nrf2. |
| 288 | abolishes repression of nfe2l2/nrf2-dependent gene expression. slows down degradation of nfe2l2/nrf2. |
| 308 | loss of export from nucleus; when associated with a-310. |
| 310 | loss of export from nucleus; when associated with a-308. |
| 334 | loss of interaction with nfe2l2/nrf2. strongly reduces repression of nfe2l2/nrf2-dependent gene expression. loss of inte |
| 380 | loss of interaction with nfe2l2/nrf2. abolishes repression of nfe2l2/nrf2-dependent gene expression. impaired interactio |
| 382 | loss of interaction with nfe2l2/nrf2. strongly reduces repression of nfe2l2/nrf2-dependent gene expression. impaired int |
| 415 | loss of interaction with nfe2l2/nrf2. abolishes repression of nfe2l2/nrf2-dependent gene expression. loss of interaction |
| 436 | loss of interaction with nfe2l2/nrf2. abolishes repression of nfe2l2/nrf2-dependent gene expression. does not affect int |
| 478 | abolishes repression of nfe2l2/nrf2-dependent gene expression. |
| 483 | loss of interaction with nfe2l2/nrf2. abolishes repression of nfe2l2/nrf2-dependent gene expression. loss of interaction |
| 525 | loss of interaction with nfe2l2/nrf2. strongly reduces repression of nfe2l2/nrf2-dependent gene expression. abolishes in |
| 572 | loss of interaction with nfe2l2/nrf2. strongly reduces repression of nfe2l2/nrf2-dependent gene expression. loss of inte |
| 615 | decreases binding to pgcka1. increases protein half-life. |
Function
Pathways and Gene Ontology
Reactome pathways
19 pathways
| ID | Pathway |
|---|---|
| R-HSA-5689880 | Ub-specific processing proteases |
| R-HSA-8951664 | Neddylation |
| R-HSA-9679191 | Potential therapeutics for SARS |
| R-HSA-9755511 | KEAP1-NFE2L2 pathway |
| R-HSA-9759194 | Nuclear events mediated by NFE2L2 |
| R-HSA-983168 | Antigen processing: Ubiquitination & Proteasome degradation |
| R-HSA-1280218 | Adaptive Immune System |
| R-HSA-1643685 | Disease |
| R-HSA-168256 | Immune System |
| R-HSA-2262752 | Cellular responses to stress |
| R-HSA-392499 | Metabolism of proteins |
| R-HSA-5663205 | Infectious disease |
| R-HSA-5688426 | Deubiquitination |
| R-HSA-597592 | Post-translational protein modification |
| R-HSA-8953897 | Cellular responses to stimuli |
| R-HSA-9679506 | SARS-CoV Infections |
| R-HSA-9711123 | Cellular response to chemical stress |
| R-HSA-9824446 | Viral Infection Pathways |
| R-HSA-983169 | Class I MHC mediated antigen processing & presentation |
MSigDB gene sets: 0 (showing top):
GO Biological Process (14): negative regulation of transcription by RNA polymerase II (GO:0000122), in utero embryonic development (GO:0001701), ubiquitin-dependent protein catabolic process (GO:0006511), regulation of autophagy (GO:0010506), protein ubiquitination (GO:0016567), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), cellular response to oxidative stress (GO:0034599), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of epidermal cell differentiation (GO:0045604), cellular response to interleukin-4 (GO:0071353), negative regulation of response to oxidative stress (GO:1902883), regulation of DNA-templated transcription (GO:0006355), response to oxidative stress (GO:0006979), protein K48-linked ubiquitination (GO:0070936)
GO Molecular Function (6): identical protein binding (GO:0042802), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), disordered domain specific binding (GO:0097718), transcription regulator inhibitor activity (GO:0140416), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)
GO Cellular Component (11): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), actin filament (GO:0005884), inclusion body (GO:0016234), midbody (GO:0030496), Cul3-RING ubiquitin ligase complex (GO:0031463), centriolar satellite (GO:0034451), nucleus (GO:0005634), protein-containing complex (GO:0032991)
Reactome top-level categories
Rollup of top-14 pathways:
| Category | Pathways |
|---|---|
| Post-translational protein modification | 2 |
| Deubiquitination | 1 |
| SARS-CoV Infections | 1 |
| Cellular response to chemical stress | 1 |
| KEAP1-NFE2L2 pathway | 1 |
| Class I MHC mediated antigen processing & presentation | 1 |
| Immune System | 1 |
| Cellular responses to stimuli | 1 |
| Disease | 1 |
| Metabolism of proteins | 1 |
| Viral Infection Pathways | 1 |
| Cellular responses to stress | 1 |
| Infectious disease | 1 |
| Adaptive Immune System | 1 |
GO top-level categories
Rollup of top GO terms by namespace:
| Category | Terms |
|---|---|
| cellular anatomical structure | 5 |
| response to oxidative stress | 2 |
| regulation of gene expression | 2 |
| intracellular anatomical structure | 2 |
| cytoplasm | 2 |
| intracellular membrane-bounded organelle | 2 |
| regulation of transcription by RNA polymerase II | 1 |
| transcription by RNA polymerase II | 1 |
| negative regulation of DNA-templated transcription | 1 |
| chordate embryonic development | 1 |
| protein ubiquitination | 1 |
| modification-dependent protein catabolic process | 1 |
| autophagy | 1 |
| regulation of catabolic process | 1 |
| protein modification by small protein conjugation | 1 |
| regulation of proteasomal ubiquitin-dependent protein catabolic process | 1 |
| proteasome-mediated ubiquitin-dependent protein catabolic process | 1 |
| positive regulation of proteasomal protein catabolic process | 1 |
| positive regulation of ubiquitin-dependent protein catabolic process | 1 |
| cellular response to chemical stress | 1 |
| ubiquitin-dependent protein catabolic process | 1 |
| proteasomal protein catabolic process | 1 |
| epidermal cell differentiation | 1 |
| regulation of epithelial cell differentiation | 1 |
| regulation of epidermis development | 1 |
| response to interleukin-4 | 1 |
| cellular response to cytokine stimulus | 1 |
| negative regulation of response to stimulus | 1 |
| regulation of response to oxidative stress | 1 |
| DNA-templated transcription | 1 |
| regulation of RNA biosynthetic process | 1 |
| response to stress | 1 |
| protein polyubiquitination | 1 |
| protein binding | 1 |
| DNA-binding transcription factor binding | 1 |
| protein domain specific binding | 1 |
| transcription regulator activity | 1 |
| molecular function inhibitor activity | 1 |
| enzyme-substrate adaptor activity | 1 |
| binding | 1 |
Protein interactions and networks
STRING
3612 interactions, top by confidence (×1000):
| Protein A | Protein B | Partner UniProt | Score |
|---|---|---|---|
| KEAP1 | NEIL2 | Q969S2 | 999 |
| KEAP1 | NFE2L2 | Q16236 | 999 |
| KEAP1 | CUL3 | Q13618 | 998 |
| KEAP1 | RBX1 | P62877 | 996 |
| KEAP1 | SQSTM1 | Q13501 | 995 |
| KEAP1 | PGAM5 | Q96HS1 | 993 |
| KEAP1 | IKBKB | O14920 | 983 |
| KEAP1 | PALB2 | Q86YC2 | 962 |
| KEAP1 | NQO1 | P15559 | 954 |
| KEAP1 | PTMA | P06454 | 936 |
| KEAP1 | HMOX1 | P09601 | 934 |
| KEAP1 | GCLM | P48507 | 932 |
| KEAP1 | RELA | Q04206 | 932 |
| KEAP1 | DPP3 | Q9NY33 | 919 |
| KEAP1 | PARK7 | Q99497 | 914 |
IntAct
507 interactions, top by confidence:
| A | B | Type | Score |
|---|---|---|---|
| NFE2L2 | KEAP1 | psi-mi:“MI:0915”(physical association) | 0.980 |
| KEAP1 | NFE2L2 | psi-mi:“MI:0915”(physical association) | 0.980 |
| KEAP1 | NFE2L2 | psi-mi:“MI:0407”(direct interaction) | 0.980 |
| NFE2L2 | KEAP1 | psi-mi:“MI:0914”(association) | 0.980 |
| KEAP1 | NFE2L2 | psi-mi:“MI:0914”(association) | 0.980 |
| SQSTM1 | KEAP1 | psi-mi:“MI:0915”(physical association) | 0.970 |
| KEAP1 | SQSTM1 | psi-mi:“MI:0915”(physical association) | 0.970 |
| KEAP1 | SQSTM1 | psi-mi:“MI:0407”(direct interaction) | 0.970 |
| KEAP1 | DPP3 | psi-mi:“MI:0915”(physical association) | 0.910 |
| DPP3 | KEAP1 | psi-mi:“MI:0915”(physical association) | 0.910 |
| KEAP1 | ETF1 | psi-mi:“MI:0915”(physical association) | 0.830 |
| MAD2L1 | KEAP1 | psi-mi:“MI:0915”(physical association) | 0.830 |
| KEAP1 | MAD2L1 | psi-mi:“MI:0915”(physical association) | 0.830 |
| KEAP1 | WDR83 | psi-mi:“MI:0915”(physical association) | 0.780 |
BioGRID (903): NFE2L2 (Biochemical Activity), KEAP1 (Affinity Capture-MS), KEAP1 (Two-hybrid), KEAP1 (Two-hybrid), KEAP1 (Two-hybrid), KEAP1 (Two-hybrid), KEAP1 (Two-hybrid), KEAP1 (Two-hybrid), KEAP1 (Two-hybrid), KEAP1 (Two-hybrid), DPP3 (Two-hybrid), NUDT4 (Two-hybrid), MAPKBP1 (Two-hybrid), KLHL3 (Two-hybrid), LSM3 (Two-hybrid)
ESM2 similar proteins: A0A2R8Q1W5, A6QQY2, B0WWP2, B3NDN0, B4HIK1, B4L0G9, B4LIG6, B4PD06, D3Z8N4, E0CZ16, E1B932, E7F6F9, E9Q4F2, F1LZ52, O94889, P28575, P57790, P59280, Q08DK3, Q14145, Q16RL8, Q2T9Z7, Q53G59, Q5R774, Q5R7B8, Q5U374, Q5ZKD9, Q5ZLD3, Q684M4, Q6DFF6, Q6JEL2, Q6JEL3, Q6NRH0, Q6TDP3, Q6TDP4, Q6ZPT1, Q7QGL0, Q80TF4, Q8BZM0, Q8K430
Diamond homologs: A0A2R8Q1W5, A9JRD8, B0WWP2, B3DIV9, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, D3Z8N4, D3ZUU2, E0CZ16, E1B932, E7F6F9, E9Q4F2, F1LZ52, F1LZF0, F1MBP6, G3X9X1, O15062, O93567, O94889, O95198, P28575, P57790, Q04652, Q08DK3, Q13105, Q14145, Q16RL8, Q1ECZ2, Q2M0J9, Q2TBA0, Q3SWU4, Q3ZB90
SIGNOR signaling
13 interactions.
| A | Effect | B | Mechanism |
|---|---|---|---|
| KEAP1 | down-regulates | NFE2L2 | binding |
| KEAP1 | “down-regulates quantity” | NFE2L2 | ubiquitination |
| DPP3 | “down-regulates quantity by destabilization” | KEAP1 | cleavage |
| BAP1 | “up-regulates quantity by stabilization” | KEAP1 | binding |
| KEAP1 | “form complex” | CUL3-RBX1-KEAP1 | binding |
| “hydrogen peroxide” | “up-regulates activity” | KEAP1 | “chemical modification” |
| SQSTM1 | “down-regulates quantity by destabilization” | KEAP1 | ubiquitination |
| KEAP1 | “up-regulates activity” | CUL3 | binding |
| KEAP1 | “down-regulates quantity by destabilization” | PGAM5 | binding |
| KEAP1 | “up-regulates activity” | “Cullin 3-RBX1-Skp1” | binding |
Enriched among interaction partners
Reactome pathways and GO biological processes over-represented among this gene’s 117 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.
Reactome pathways:
| Pathway | Partners | Fold | FDR |
|---|---|---|---|
| KEAP1-NFE2L2 pathway | 11 | 17.4× | 2e-08 |
| Cellular response to chemical stress | 7 | 13.2× | 3e-04 |
| Neddylation | 9 | 5.6× | 4e-03 |
| Cellular responses to stress | 10 | 4.8× | 4e-03 |
| Cellular responses to stimuli | 11 | 4.5× | 4e-03 |
GO biological processes:
| GO term | Partners | Fold | FDR |
|---|---|---|---|
| cellular response to amino acid stimulus | 5 | 16.5× | 5e-03 |
Disease & clinical
Cancer significance
From intOGen — cancer-driver classification: activating (oncogene-like) across 6 cancer types — CHOL, HCC, LUAD, LUSC, NPC, NSCLC.
Clinical variants and AI predictions
ClinVar
80 variants total. Per-class counts are floors (≥ shown; pagination cap):
| Classification | Count (floor) |
|---|---|
| Pathogenic | 0 |
| Likely pathogenic | 0 |
| Uncertain significance | 49 |
| Likely benign | 9 |
| Benign | 1 |
Top pathogenic / likely-pathogenic (0)
SpliceAI
838 predictions. Top by Δscore:
| Variant | Effect | Δscore |
|---|---|---|
| 19:10486814:GCCTC:G | acceptor_gain | 1.0000 |
| 19:10486815:CCTCC:C | acceptor_gain | 1.0000 |
| 19:10486816:CTC:C | acceptor_gain | 1.0000 |
| 19:10486817:TC:T | acceptor_gain | 1.0000 |
| 19:10486818:CC:C | acceptor_gain | 1.0000 |
| 19:10486818:CCT:C | acceptor_loss | 1.0000 |
| 19:10486819:C:CA | acceptor_loss | 1.0000 |
| 19:10486819:C:CC | acceptor_gain | 1.0000 |
| 19:10486820:T:G | acceptor_loss | 1.0000 |
| 19:10486822:C:CT | acceptor_gain | 1.0000 |
| 19:10486823:G:T | acceptor_gain | 1.0000 |
| 19:10489188:TCACC:T | donor_loss | 1.0000 |
| 19:10489189:CACCA:C | donor_loss | 1.0000 |
| 19:10489190:ACCAA:A | donor_loss | 1.0000 |
| 19:10489209:C:A | donor_gain | 1.0000 |
| 19:10489366:CGC:C | acceptor_gain | 1.0000 |
| 19:10489367:GCC:G | acceptor_loss | 1.0000 |
| 19:10489368:CCTAA:C | acceptor_loss | 1.0000 |
| 19:10489369:C:A | acceptor_loss | 1.0000 |
| 19:10489369:C:CC | acceptor_gain | 1.0000 |
| 19:10489370:T:G | acceptor_loss | 1.0000 |
| 19:10489658:T:TA | donor_gain | 1.0000 |
| 19:10491572:CTCA:C | donor_loss | 1.0000 |
| 19:10491573:TCACC:T | donor_loss | 1.0000 |
| 19:10491574:CACCT:C | donor_loss | 1.0000 |
| 19:10491575:A:AC | donor_gain | 1.0000 |
| 19:10491575:ACCTC:A | donor_loss | 1.0000 |
| 19:10491576:C:CC | donor_gain | 1.0000 |
| 19:10491576:CCT:C | donor_gain | 1.0000 |
| 19:10499396:T:TA | donor_gain | 1.0000 |
AlphaMissense
4110 scored. Top likely-pathogenic:
| Variant | Protein change | am_pathogenicity |
|---|---|---|
| 19:10486719:C:T | G603E | 1.000 |
| 19:10486756:A:G | W591R | 1.000 |
| 19:10486756:A:T | W591R | 1.000 |
| 19:10486796:G:C | F577L | 1.000 |
| 19:10486796:G:T | F577L | 1.000 |
| 19:10486798:A:G | F577L | 1.000 |
| 19:10486815:C:A | G571V | 1.000 |
| 19:10486815:C:T | G571D | 1.000 |
| 19:10486818:C:A | G570V | 1.000 |
| 19:10486818:C:T | G570E | 1.000 |
| 19:10489332:C:T | G523E | 1.000 |
| 19:10489333:C:A | G523W | 1.000 |
| 19:10489653:C:T | G509E | 1.000 |
| 19:10489688:C:A | W497C | 1.000 |
| 19:10489688:C:G | W497C | 1.000 |
| 19:10489690:A:G | W497R | 1.000 |
| 19:10489690:A:T | W497R | 1.000 |
| 19:10489745:A:C | F478L | 1.000 |
| 19:10489745:A:T | F478L | 1.000 |
| 19:10489747:A:G | F478L | 1.000 |
| 19:10489749:C:T | G477D | 1.000 |
| 19:10489752:C:T | G476E | 1.000 |
| 19:10489753:C:A | G476W | 1.000 |
| 19:10489794:C:T | G462E | 1.000 |
| 19:10489795:C:A | G462W | 1.000 |
| 19:10489799:C:A | R460S | 1.000 |
| 19:10489799:C:G | R460S | 1.000 |
| 19:10489800:C:A | R460M | 1.000 |
| 19:10489800:C:G | R460T | 1.000 |
| 19:10489831:A:G | W450R | 1.000 |
dbSNP variants (sampled 300 via entrez): RS1000081810 (19:10504656 G>C), RS1000115630 (19:10496793 C>G,T), RS1000177106 (19:10504982 T>C), RS1000277602 (19:10498182 G>A), RS1000416320 (19:10485993 C>T), RS1000433910 (19:10490980 A>G), RS1000653506 (19:10493123 G>A,C), RS1000764295 (19:10492600 C>G), RS1000787528 (19:10485773 G>C), RS1000818506 (19:10493061 T>A), RS1000943167 (19:10492800 TAG>T), RS1001151960 (19:10487358 A>G), RS1001155321 (19:10496208 AAAAAAGGCCAGGTGC>A), RS1001332821 (19:10488281 C>G), RS1001397882 (19:10487228 C>A)
Disease associations
OMIM: gene MIM:606016 | disease phenotypes:
GenCC curated gene-disease
| Disease | Classification | Inheritance |
|---|---|---|
| goiter, multinodular 1, with or without Sertoli-Leydig cell tumors | Supportive | Autosomal dominant |
Mondo (1): goiter, multinodular 1, with or without Sertoli-Leydig cell tumors (MONDO:0007681)
Orphanet (0):
HPO phenotypes
14 total (14 of 14 shown, HPO-id order):
| HPO | Term |
|---|---|
| HP:0000836 | Hyperthyroidism |
| HP:0002671 | Basal cell carcinoma |
| HP:0002890 | Thyroid carcinoma |
| HP:0005584 | Renal cell carcinoma |
| HP:0005987 | Multinodular goiter |
| HP:0006779 | Alveolar rhabdomyosarcoma |
| HP:0007129 | Cerebellar medulloblastoma |
| HP:0030071 | Medulloepithelioma |
| HP:0030434 | Pilomatrixoma |
| HP:0100528 | Pleuropulmonary blastoma |
| HP:0100615 | Ovarian neoplasm |
| HP:0100617 | Testicular seminoma |
| HP:0100619 | Sertoli cell neoplasm |
| HP:0200063 | Colorectal polyposis |
GWAS associations
6 associations (top):
| Study | Trait | p-value |
|---|---|---|
| GCST004131_88 | Inflammatory bowel disease | 2.000000e-11 |
| GCST004132_111 | Crohn’s disease | 3.000000e-13 |
| GCST005537_48 | Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy) | 6.000000e-09 |
| GCST006430_8 | Body mass index and waist-hip ratio (pleiotropy) | 5.000000e-06 |
| GCST012190_13 | Body mass index and diastolic blood pressure (bivariate analysis) | 5.000000e-06 |
| GCST012191_13 | Body mass index and systolic blood pressure (bivariate analysis) | 5.000000e-06 |
EFO canonical traits (4, from GWAS)
| EFO ID | Trait name |
|---|---|
| EFO:0004340 | body mass index |
| EFO:0004343 | waist-hip ratio |
| EFO:0006336 | diastolic blood pressure |
| EFO:0006335 | systolic blood pressure |
MeSH disease descriptors (1)
| Descriptor | Name | Tree numbers |
|---|---|---|
| C562732 | Euthyroid Goiter (supp.) |
Drugs & pharmacology
Drug and pharmacology data
Is drug target: yes
ChEMBL targets (7): CHEMBL2069156 (SINGLE PROTEIN), CHEMBL3038498 (PROTEIN-PROTEIN INTERACTION), CHEMBL4106129 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296122 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296123 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193832 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193838 (PROTEIN-PROTEIN INTERACTION)
Molecules with ChEMBL bioactivity
9 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 391,615 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).
| Molecule | Name | Phase | Patents |
|---|---|---|---|
| CHEMBL1200969 | DUTASTERIDE | 4 | 11,156 |
| CHEMBL157101 | KETOCONAZOLE | 4 | 75,361 |
| CHEMBL1607 | TOPOTECAN HYDROCHLORIDE | 4 | 56,379 |
| CHEMBL2107333 | DIMETHYL FUMARATE | 4 | 22,969 |
| CHEMBL359744 | DOXORUBICIN HYDROCHLORIDE | 4 | 141,917 |
| CHEMBL603 | ZAFIRLUKAST | 4 | 23,220 |
| CHEMBL932 | DIPYRIDAMOLE | 4 | 51,743 |
| CHEMBL48802 | SULFORAPHANE | 3 | 7,981 |
| CHEMBL1093059 | BARDOXOLONE | 2 | 889 |
Clinical evidence (CIViC)
Drug × variant × indication: 4 predictive associations from 4 curated evidence items.
| Variant | Therapy | Indication | Effect | Level | CIViC |
|---|---|---|---|---|---|
| KEAP1 Mutation | Durvalumab Regimen + Chemotherapy + Tremelimumab | Lung Non-small Cell Carcinoma | Sensitivity/Response | CIViC A | EID12419 |
| KEAP1 Mutation | Cisplatin/Pembrolizumab/Pemetrexed Regimen | Lung Non-small Cell Carcinoma | Resistance | CIViC B | EID12339 |
| NFE2L2 Mutation OR KEAP1 Mutation OR CUL3 Mutation | Platinum Doublet | Lung Non-small Cell Carcinoma | Resistance | CIViC B | EID12558 |
| KEAP1 Mutation | NSC84167 | Lung Non-small Cell Carcinoma | Sensitivity/Response | CIViC D | EID12575 |
PharmGKB: 1 entry (VIP=true, CPIC=false)
GtoPdb / IUPHAR curated pharmacology
(IUPHAR/BPS Guide to Pharmacology — expert-curated)
Target class: other protein — Kelch-like proteins
Most potent curated ligand interactions (7 total), top 7:
| Ligand | Action | Affinity | Parameter |
|---|---|---|---|
| biKEAP1 | Binding | 8.07 | pIC50 |
| compound 10 [PMID: 31411465] | Binding | 7.72 | pKd |
| Nrf2 peptide [PMID: 23647822] | Binding | 7.48 | pIC50 |
| CPUY192018 | Binding | 7.4 | pKd |
| bardoxolone | Binding | 7.0 | pIC50 |
| isoquinoline 17 [PMID: 30122040] | Binding | 6.99 | pKd |
| RA839 | Binding | 5.22 | pKd |
Binding affinities (BindingDB)
372 measured of 462 human assays (462 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.
| Ligand | Measure | Value | Patent |
|---|---|---|---|
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-(4-chloro-1-methylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3R)-3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-2,3-dihydro-1H-inden-5-yl]-3-(1,4-dimethylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(4R)-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-2,3-dihydro-1H-inden-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(4R)-4-ethyl-8-methyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-2,3-dihydro-1H-inden-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(4R)-4-ethyl-7-methyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-2,3-dihydro-1H-inden-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-5,1lambda6,2-benzoxathiazepin-2-yl]methyl]-2,3-dihydro-1H-inden-5-yl]-3-(1,4-dimethylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(4R)-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3R)-3-[7-[[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-5,1lambda6,2-benzoxathiazepin-2-yl]methyl]-2,3-dihydro-1H-inden-5-yl]-3-(1,4-dimethylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(4R)-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-2,3-dihydro-1H-inden-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(4R)-4-ethyl-1,1-dioxo-8-(trifluoromethyl)-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-2,3-dihydro-1H-inden-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[(4,4-dimethyl-1,1-dioxo-3H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl]-2,3-dihydro-1H-inden-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[(1,1-dioxospiro[3H-pyrido[2,3-b][1,4,5]oxathiazepine-4,1’-cyclobutane]-2-yl)methyl]-2,3-dihydro-1H-inden-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[(1,1-dioxospiro[3H-pyrido[2,3-b][1,4,5]oxathiazepine-4,3’-oxetane]-2-yl)methyl]-2,3-dihydro-1H-inden-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3R)-3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-2,3-dihydro-1H-inden-5-yl]-3-(7-cyclopropyl-1,4-dimethylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3S)-3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-2,3-dihydro-1H-inden-5-yl]-3-(7-cyclopropyl-1,4-dimethylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3S)-3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-[1,4-dimethyl-7-(trifluoromethoxy)benzotriazol-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-(7-methoxy-1,4-dimethylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(7-chloro-1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-(7-cyano-1,4-dimethylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-[1,4-dimethyl-7-(trifluoromethyl)benzotriazol-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-[1,4-dimethyl-7-(trifluoromethoxy)benzotriazol-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-[7-(difluoromethoxy)-1,4-dimethylbenzotriazol-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-[1-(2-hydroxy-2-methylpropyl)-4-methylbenzotriazol-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| ethyl 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-[4-methyl-1-(3-methylsulfonylpropyl)benzotriazol-5-yl]propanoate | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-(3,7-dimethyltriazolo[4,5-b]pyridin-6-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzothiophen-5-yl]-3-[4-methyl-1-(2,2,2-trifluoroethyl)benzotriazol-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(2R,5S)-2-ethyl-5-methyl-3,5-dihydro-2H-pyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3R)-3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(2R,5S)-2-ethyl-5-methyl-3,5-dihydro-2H-pyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3R)-3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(2R,5S)-2-ethyl-5-methyl-3,5-dihydro-2H-pyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-2,3-dihydro-1H-inden-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| ethyl (3S)-3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(2R,5S)-2-ethyl-5-methyl-3,5-dihydro-2H-pyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-2,3-dihydro-1H-inden-5-yl]propanoate | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3R)-3-(1,4-dimethyl-2,3-dihydrobenzotriazol-5-yl)-3-[7-[[(2R)-2-ethyl-5-methyl-7-oxo-2,3,5,6-tetrahydropyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3R)-3-(1,4-dimethyl-2,3-dihydrobenzotriazol-5-yl)-3-[7-[[(2R,5S)-2,5-dimethyl-7-oxo-2,3,5,6-tetrahydropyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3R)-3-(3,7-dimethyl-1,2-dihydrotriazolo[4,5-b]pyridin-6-yl)-3-[7-[[(2R)-2-ethyl-5-methyl-7-oxo-2,3,5,6-tetrahydropyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| ethyl (3R)-3-(1,4-dimethyl-2,3-dihydrobenzotriazol-5-yl)-3-[7-[[(2R,5S)-2,5-dimethyl-7-oxo-2,3,5,6-tetrahydropyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]propanoate | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| ethyl (3R)-3-[7-[[(2R)-2-cyclopropyl-5-methyl-7-oxo-2,3,5,6-tetrahydropyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]-3-(3,7-dimethyl-1,2-dihydrotriazolo[4,5-b]pyridin-6-yl)propanoate | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3R)-3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(5R)-5-methyl-7-oxospiro[5,6-dihydro-3H-pyrido[2,3-f][1,4]oxazepine-2,1’-cyclopropane]-4-yl]methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-(1,4-dimethylbenzotriazol-5-yl)-3-[4-[[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-5,1lambda6,2-benzoxathiazepin-2-yl]methyl]-1H-indol-6-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-2,3-dihydro-1-benzofuran-5-yl]-3-(1,4-dimethylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| 3-[7-[[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydropyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl]-1-benzofuran-5-yl]-3-(4-chloro-1-methylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| tert-butyl 6-[1-(7-cyclopropyl-1,4-dimethylbenzotriazol-5-yl)-3-ethoxy-3-oxopropyl]-4-[[(2R,5S)-2-ethyl-5-methyl-3,5-dihydro-2H-pyrido[2,3-f][1,4]oxazepin-4-yl]methyl]indole-1-carboxylate | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3R)-3-(7-cyclopropyl-1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(2R,5S)-2-ethyl-5-methyl-3,5-dihydro-2H-pyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-2,3-dihydro-1H-inden-5-yl]propanoic acid | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| ethyl 3-(7-cyclopropyl-1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(2R,5S)-2-ethyl-5-methyl-3,5-dihydro-2H-pyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-2,3-dihydro-1-benzofuran-5-yl]propanoate | IC50 | 20 nM | US-20250092064: BENZOTRIAZOLE COMPOUND |
| (3S)-3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[[(2R)-2-ethyl-7-oxo-2,3,5,6-tetrahydropyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250296939: BENZOTHIOPHENE COMPOUND |
| (3S)-3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[(7-oxospiro[5,6-dihydro-3H-pyrido[2,3-f][1,4]oxazepine-2,1’-cyclopropane]-4-yl)methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250296939: BENZOTHIOPHENE COMPOUND |
| (3R)-3-(1,4-dimethylbenzotriazol-5-yl)-3-[7-[(7-oxospiro[5,6-dihydro-3H-pyrido[2,3-f][1,4]oxazepine-2,1’-cyclopropane]-4-yl)methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250296939: BENZOTHIOPHENE COMPOUND |
| (3R)-3-[7-[[(2R)-2-cyclopropyl-7-oxo-2,3,5,6-tetrahydropyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]-3-(1,4-dimethylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250296939: BENZOTHIOPHENE COMPOUND |
| (3S)-3-[7-[[(2R)-2-cyclopropyl-7-oxo-2,3,5,6-tetrahydropyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]-3-(1,4-dimethylbenzotriazol-5-yl)propanoic acid | IC50 | 20 nM | US-20250296939: BENZOTHIOPHENE COMPOUND |
| (3R)-3-[7-[[(2R)-2-cyclopropyl-7-oxo-2,3,5,6-tetrahydropyrido[2,3-f][1,4]oxazepin-4-yl]methyl]-1-benzothiophen-5-yl]-3-(3,7-dimethyltriazolo[4,5-b]pyridin-6-yl)propanoic acid | IC50 | 20 nM | US-20250296939: BENZOTHIOPHENE COMPOUND |
| (3S)-3-(1,4-dimethylbenzotriazol-5-yl)-2,2-dimethyl-3-[7-[(7-oxospiro[5,6-dihydro-3H-pyrido[2,3-f][1,4]oxazepine-2,1’-cyclopropane]-4-yl)methyl]-1-benzothiophen-5-yl]propanoic acid | IC50 | 20 nM | US-20250296939: BENZOTHIOPHENE COMPOUND |
ChEMBL bioactivities
1612 potent at pChembl≥5 of 1964 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).
PubChem BioAssay actives
989 with measured affinity, of 3094 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.
| Compound | Assay | Type | Value | Unit |
|---|---|---|---|---|
| (2S,3S)-3-(1-ethyl-4-methylbenzotriazol-5-yl)-2-methyl-3-[2-(2,3,5,6-tetramethylbenzoyl)-3,4-dihydro-1H-isoquinolin-7-yl]propanoic acid | 1651179: Binding affinity to Keap1 (unknown origin) by SPR assay | kd | 0.0001 | uM |
| 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]-3-[3-(1,3-dioxoisoindol-2-yl)propyl]naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid | 2008554: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) preincubated for 30 mins followed by Terbium labeled anti-His antibody addition for 30 mins prior to fluorescein labeled-9mer Nrf2 peptide addition and measured after 60 mins by TR-FRET assay | ki | 0.0001 | uM |
| (3S)-1-[4-[(2,3,5,6-tetramethylphenyl)sulfonylamino]naphthalen-1-yl]pyrrolidine-3-carboxylic acid | 1676325: Inhibition of FITC-9mer Nrf2 peptide interaction with human recombinant Keap1 Kelch domain (321 to 609 residues) expressed in Escherichia coli DE3 cells incubated for 30 mins by fluorescence polarization assay | ic50 | 0.0001 | uM |
| (3S)-3-(1-ethyl-4-methylbenzotriazol-5-yl)-3-[2-(2,3,5,6-tetramethylbenzoyl)-3,4-dihydro-1H-isoquinolin-7-yl]propanoic acid | 1651179: Binding affinity to Keap1 (unknown origin) by SPR assay | kd | 0.0007 | uM |
| (2S)-2-[(S)-(1-ethyl-4-methylbenzotriazol-5-yl)-[2-(2,3,5,6-tetramethylbenzoyl)-3,4-dihydro-1H-isoquinolin-7-yl]methyl]butanoic acid | 1651179: Binding affinity to Keap1 (unknown origin) by SPR assay | kd | 0.0009 | uM |
| (3S)-3-(7-methoxy-1-methylbenzotriazol-5-yl)-3-[4-methyl-3-[[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-5,1lambda6,2-benzoxathiazepin-2-yl]methyl]phenyl]propanoic acid | 1577815: Inhibition of Cys5-LDEETGEFL-NH2 binding to recombinant human KEAP1 Kelch domain (321 to 609 residues) expressed in Escherichia coli BL21 (DE3) measured after 10 to 15 mins by fluorescence polarization assay | ki | 0.0010 | uM |
| (2R,3S)-3-[3-[(1-cyanocyclopropyl)methoxy]-4-methylphenyl]-3-[[(2S)-2-fluoro-2-(4-methylphenyl)acetyl]amino]-2-methylpropanoic acid | 2080975: Binding affinity to biotinylated Keap1 Kelch domain (unknown origin) by SPR method | kd | 0.0010 | uM |
| 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid | 2088407: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) assessed as inhibition constant by TR-FRET assay | ki | 0.0010 | uM |
| 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]-3-phenylsulfanylnaphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid | 2008554: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) preincubated for 30 mins followed by Terbium labeled anti-His antibody addition for 30 mins prior to fluorescein labeled-9mer Nrf2 peptide addition and measured after 60 mins by TR-FRET assay | ki | 0.0015 | uM |
| (2R,3S)-3-(1-ethyl-4-methylbenzotriazol-5-yl)-2-methyl-3-[2-(2,3,5,6-tetramethylbenzoyl)-3,4-dihydro-1H-isoquinolin-7-yl]propanoic acid | 1651179: Binding affinity to Keap1 (unknown origin) by SPR assay | kd | 0.0019 | uM |
| 2-[[3-(carboxymethoxy)-4-[carboxymethyl-(4-methylphenyl)sulfonylamino]naphthalen-1-yl]-(4-methylphenyl)sulfonylamino]acetic acid | 2088408: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) assessed as inhibition constant by fluorescence polarization assay | ki | 0.0019 | uM |
| 3-[5-fluoro-3-(1-methylpyrazol-4-yl)-2-pyridinyl]-3-methoxy-5,5-dimethyl-6-oxocyclohexene-1-carbonitrile | 1511440: Inhibition of KEAP1 interaction with Nrf2 in human HEK293 cells transfected with ARE-LUC assessed as activation of Nrf2 signaling pathway measured after 18 hrs by steady-Glo luciferase assay | ec50 | 0.0020 | uM |
| 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]-3-(3-morpholin-4-yl-3-oxopropyl)naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid | 2008554: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) preincubated for 30 mins followed by Terbium labeled anti-His antibody addition for 30 mins prior to fluorescein labeled-9mer Nrf2 peptide addition and measured after 60 mins by TR-FRET assay | ki | 0.0020 | uM |
| (3S)-3-[5-fluoro-3-(1,2-thiazol-5-yl)-2-pyridinyl]-3-methoxy-5,5-dimethyl-6-oxocyclohexene-1-carbonitrile | 1511440: Inhibition of KEAP1 interaction with Nrf2 in human HEK293 cells transfected with ARE-LUC assessed as activation of Nrf2 signaling pathway measured after 18 hrs by steady-Glo luciferase assay | ec50 | 0.0020 | uM |
| 1-(4-ethoxyphenyl)sulfonyl-5-[(4-ethoxyphenyl)sulfonylamino]-N-hydroxy-2-methylbenzo[g]indole-3-carboxamide | 1577815: Inhibition of Cys5-LDEETGEFL-NH2 binding to recombinant human KEAP1 Kelch domain (321 to 609 residues) expressed in Escherichia coli BL21 (DE3) measured after 10 to 15 mins by fluorescence polarization assay | ki | 0.0021 | uM |
| 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]-3-[4-(1,3-dioxoisoindol-2-yl)phenyl]naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid | 2008554: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) preincubated for 30 mins followed by Terbium labeled anti-His antibody addition for 30 mins prior to fluorescein labeled-9mer Nrf2 peptide addition and measured after 60 mins by TR-FRET assay | ki | 0.0021 | uM |
| 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]-3-phenylnaphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid | 2008554: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) preincubated for 30 mins followed by Terbium labeled anti-His antibody addition for 30 mins prior to fluorescein labeled-9mer Nrf2 peptide addition and measured after 60 mins by TR-FRET assay | ki | 0.0024 | uM |
| 8,8-dimethyl-4-(4-methyl-3-pyridinyl)-9-oxo-1-oxa-4-azaspiro[5.5]undec-10-ene-10-carbonitrile | 1828011: Modulation of Keap1-Nrf2 protein-protein interaction in human U2OS cells assessed as inhibition of Keap1 by PathHunter assay | ec50 | 0.0025 | uM |
| (3S)-3-(2-benzoyl-3,4-dihydro-1H-isoquinolin-7-yl)-3-(1-ethyl-4-methylbenzotriazol-5-yl)propanoic acid | 1651179: Binding affinity to Keap1 (unknown origin) by SPR assay | kd | 0.0027 | uM |
| (7R,10S,16S,19S,22S,25S,28S)-28-amino-10,19-bis(2-carboxyethyl)-25-(carboxymethyl)-16-[(1R)-1-hydroxyethyl]-22-(hydroxymethyl)-9,12,15,18,21,24,27-heptaoxo-2-oxa-5-thia-8,11,14,17,20,23,26-heptazabicyclo[28.2.2]tetratriaconta-1(32),30,33-triene-7-carboxylic acid | 1856128: Inhibition of Keap1 (unknown origin) by ELISA analysis | ic50 | 0.0028 | uM |
| 6-chloro-5’,5’-dimethyl-6’-oxospiro[1H-2-benzofuran-3,3’-cyclohexene]-1’-carbonitrile | 1828011: Modulation of Keap1-Nrf2 protein-protein interaction in human U2OS cells assessed as inhibition of Keap1 by PathHunter assay | ec50 | 0.0029 | uM |
| 3-[(4S,7S,11S,13S,16S,19S,25S,28S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-28-carbamoyl-16-(2-carboxyethyl)-7-(carboxymethyl)-11-fluoro-19-[(1R)-1-hydroxyethyl]-5,8,14,17,20,23,26-heptaoxo-1,6,9,15,18,21,24,27,31,32-decazatricyclo[28.2.1.09,13]tritriaconta-30(33),31-dien-25-yl]propanoic acid | 1677710: Binding affinity to human KEAP1 Kelch domain (322 to 609 residues) incubated for 60 mins by TR-FRET assay | ic50 | 0.0030 | uM |
| (2R,3S)-3-[[(2S)-2-[4-[(3-ethoxy-2-pyridinyl)methyl]phenyl]-2-fluoroacetyl]amino]-2-methyl-3-(4-methylphenyl)propanoic acid | 2080975: Binding affinity to biotinylated Keap1 Kelch domain (unknown origin) by SPR method | kd | 0.0030 | uM |
| 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]-3-(4-cyanophenyl)naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid | 2008554: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) preincubated for 30 mins followed by Terbium labeled anti-His antibody addition for 30 mins prior to fluorescein labeled-9mer Nrf2 peptide addition and measured after 60 mins by TR-FRET assay | ki | 0.0031 | uM |
| 8,8-dimethyl-9-oxo-4-pyridin-3-yl-1-oxa-4-azaspiro[5.5]undec-10-ene-10-carbonitrile | 1828011: Modulation of Keap1-Nrf2 protein-protein interaction in human U2OS cells assessed as inhibition of Keap1 by PathHunter assay | ec50 | 0.0031 | uM |
| 3-[(3S,6S,12S,15S,21S,24S,27S,29S)-6-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-12-carbamoyl-24-(2-carboxyethyl)-3-(carboxymethyl)-29-fluoro-21-[(1R)-1-hydroxyethyl]-2,5,9,14,17,20,23,26-octaoxo-1,4,10,13,16,19,22,25-octazabicyclo[25.3.0]triacontan-15-yl]propanoic acid | 1677710: Binding affinity to human KEAP1 Kelch domain (322 to 609 residues) incubated for 60 mins by TR-FRET assay | ic50 | 0.0031 | uM |
| 4-(3-fluoro-4-pyridinyl)-8,8-dimethyl-9-oxo-1-oxa-4-azaspiro[5.5]undec-10-ene-10-carbonitrile | 1828011: Modulation of Keap1-Nrf2 protein-protein interaction in human U2OS cells assessed as inhibition of Keap1 by PathHunter assay | ec50 | 0.0032 | uM |
| 3-[(3S,6S,12S,15S,21S,24S,27S,29S)-6-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-12-carbamoyl-24-(2-carboxyethyl)-3-(carboxymethyl)-29-fluoro-21-[(1R)-1-hydroxyethyl]-2,5,9,14,17,20,23,26-octaoxo-1,4,10,13,16,19,22,25-octazabicyclo[25.3.0]triacontan-15-yl]propanoic acid | 1677710: Binding affinity to human KEAP1 Kelch domain (322 to 609 residues) incubated for 60 mins by TR-FRET assay | ic50 | 0.0034 | uM |
| 3-[(4S,7S,11S,13S,16S,19S,25S,28S)-4-[[2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]acetyl]amino]-28-carbamoyl-16-(2-carboxyethyl)-7-(carboxymethyl)-11-fluoro-19-[(1R)-1-hydroxyethyl]-5,8,14,17,20,23,26-heptaoxo-1,6,9,15,18,21,24,27,31,32-decazatricyclo[28.2.1.09,13]tritriaconta-30(33),31-dien-25-yl]propanoic acid | 1677710: Binding affinity to human KEAP1 Kelch domain (322 to 609 residues) incubated for 60 mins by TR-FRET assay | ic50 | 0.0036 | uM |
| 2-[[3-(3-amino-3-oxopropyl)-4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid | 2008554: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) preincubated for 30 mins followed by Terbium labeled anti-His antibody addition for 30 mins prior to fluorescein labeled-9mer Nrf2 peptide addition and measured after 60 mins by TR-FRET assay | ki | 0.0042 | uM |
| 3-[(4S,7S,11S,13S,16S,19S,25S,28S)-4-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-6-amino-2-[[(2S,3S)-2-[[(2S)-5-amino-2-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]hexanoyl]amino]-3-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylsulfanylbutanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]hexanoyl]amino]hexanoyl]amino]-28-carbamoyl-16-(2-carboxyethyl)-7-(carboxymethyl)-11-fluoro-19-[(1R)-1-hydroxyethyl]-5,8,14,17,20,23,26-heptaoxo-1,6,9,15,18,21,24,27,31,32-decazatricyclo[28.2.1.09,13]tritriaconta-30(33),31-dien-25-yl]propanoic acid | 1677710: Binding affinity to human KEAP1 Kelch domain (322 to 609 residues) incubated for 60 mins by TR-FRET assay | ic50 | 0.0042 | uM |
| 8,8-dimethyl-4-(5-methyl-3-pyridinyl)-9-oxo-1-oxa-4-azaspiro[5.5]undec-10-ene-10-carbonitrile | 1828011: Modulation of Keap1-Nrf2 protein-protein interaction in human U2OS cells assessed as inhibition of Keap1 by PathHunter assay | ec50 | 0.0045 | uM |
| 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]-3-[3-oxo-3-(propan-2-ylamino)propyl]naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid | 2008554: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) preincubated for 30 mins followed by Terbium labeled anti-His antibody addition for 30 mins prior to fluorescein labeled-9mer Nrf2 peptide addition and measured after 60 mins by TR-FRET assay | ki | 0.0046 | uM |
| 3-[(4S,7S,11S,13S,16S,19S,25S,28S)-4-[[(2S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-5-carbamimidamido-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[(2S)-2-carbamoylpyrrolidin-1-yl]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]pentanoyl]amino]acetyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-28-carbamoyl-16-(2-carboxyethyl)-7-(carboxymethyl)-11-fluoro-19-[(1R)-1-hydroxyethyl]-5,8,14,17,20,23,26-heptaoxo-1,6,9,15,18,21,24,27,31,32-decazatricyclo[28.2.1.09,13]tritriaconta-30(33),31-dien-25-yl]propanoic acid | 1677710: Binding affinity to human KEAP1 Kelch domain (322 to 609 residues) incubated for 60 mins by TR-FRET assay | ic50 | 0.0047 | uM |
| 3-[(3S,6S,12S,15S,21S,24S,27S,29S)-6-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-6-amino-2-[[(2S,3S)-2-[[(2S)-5-amino-2-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]hexanoyl]amino]-3-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylsulfanylbutanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]hexanoyl]amino]hexanoyl]amino]-12-carbamoyl-24-(2-carboxyethyl)-3-(carboxymethyl)-29-fluoro-21-[(1R)-1-hydroxyethyl]-2,5,9,14,17,20,23,26-octaoxo-1,4,10,13,16,19,22,25-octazabicyclo[25.3.0]triacontan-15-yl]propanoic acid | 1677710: Binding affinity to human KEAP1 Kelch domain (322 to 609 residues) incubated for 60 mins by TR-FRET assay | ic50 | 0.0048 | uM |
| 3-[(3S,6S,12S,15S,21S,24S,27S,29S)-6-[[2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]acetyl]amino]-12-carbamoyl-24-(2-carboxyethyl)-3-(carboxymethyl)-29-fluoro-21-[(1R)-1-hydroxyethyl]-2,5,9,14,17,20,23,26-octaoxo-1,4,10,13,16,19,22,25-octazabicyclo[25.3.0]triacontan-15-yl]propanoic acid | 1677710: Binding affinity to human KEAP1 Kelch domain (322 to 609 residues) incubated for 60 mins by TR-FRET assay | ic50 | 0.0048 | uM |
| 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]-3-(4-methoxyphenyl)naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid | 2008554: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) preincubated for 30 mins followed by Terbium labeled anti-His antibody addition for 30 mins prior to fluorescein labeled-9mer Nrf2 peptide addition and measured after 60 mins by TR-FRET assay | ki | 0.0049 | uM |
| (2S)-2-[[2-[[(2S,3R)-2-[[(2S)-2-amino-4-carboxybutanoyl]amino]-3-hydroxybutanoyl]amino]acetyl]amino]pentanedioic acid | 1204220: Binding affinity to Keap1/Nrf2 complex (unknown origin) by ITC method | kd | 0.0050 | uM |
| 8,8-dimethyl-9-oxo-4-pyridin-2-yl-1-oxa-4-azaspiro[5.5]undec-10-ene-10-carbonitrile | 1828011: Modulation of Keap1-Nrf2 protein-protein interaction in human U2OS cells assessed as inhibition of Keap1 by PathHunter assay | ec50 | 0.0058 | uM |
| 3-(3-bromo-5-fluoro-2-pyridinyl)-3-methoxy-5,5-dimethyl-6-oxocyclohexene-1-carbonitrile | 1511440: Inhibition of KEAP1 interaction with Nrf2 in human HEK293 cells transfected with ARE-LUC assessed as activation of Nrf2 signaling pathway measured after 18 hrs by steady-Glo luciferase assay | ec50 | 0.0060 | uM |
| (2R,3S)-3-[[(2S)-2-(4-chlorophenyl)-2-fluoroacetyl]amino]-3-[3-(2-cyano-2-methylpropoxy)-4-methylphenyl]-2-methylpropanoic acid | 2080975: Binding affinity to biotinylated Keap1 Kelch domain (unknown origin) by SPR method | kd | 0.0060 | uM |
| 3-[(4R,7S,13S,16S,19S,25S,28R)-4-acetamido-28-carbamoyl-16-(2-carboxyethyl)-7-(carboxymethyl)-32,33,34,35-tetrafluoro-19-[(1R)-1-hydroxyethyl]-5,8,14,17,20,23,26-heptaoxo-2,30-dithia-6,9,15,18,21,24,27-heptazatricyclo[29.2.2.09,13]pentatriaconta-1(34),31(35),32-trien-25-yl]propanoic acid | 1394077: Displacement of F-14 from Keap1 Kelch domain (unknown origin) expressed in Escherichia coli BL21 (DE3) after 15 mins by fluorescence polarization assay | ki | 0.0061 | uM |
| 3-[(3S,6S,9S,15S,18S,21S,27S,30S,33S)-9-(3-amino-3-oxopropyl)-18-benzyl-30-(2-carboxyethyl)-3-(carboxymethyl)-27-[(1R)-1-hydroxyethyl]-6,15-bis(2-methylpropyl)-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-1,4,7,10,13,16,19,22,25,28,31-undecazabicyclo[31.3.0]hexatriacontan-21-yl]propanoic acid | 1493694: Binding affinity to human biotin-labeled Keap1 Kelch domain (322 to 609 residues) expressed in Escherichia coli (DE3) by biolayer interferometry | kd | 0.0062 | uM |
| 2-[3-(carboxymethoxy)-4-[carboxymethyl-(4-methylphenyl)sulfonylamino]-N-(4-methylphenyl)sulfonylanilino]acetic acid | 2088408: Inhibition of Keap1-Nrf2 protein-protein interaction (unknown origin) assessed as inhibition constant by fluorescence polarization assay | ki | 0.0064 | uM |
| 3-[5-fluoro-3-(2-methyl-1,3-thiazol-5-yl)-2-pyridinyl]-3-methoxy-5,5-dimethyl-6-oxocyclohexene-1-carbonitrile | 1511440: Inhibition of KEAP1 interaction with Nrf2 in human HEK293 cells transfected with ARE-LUC assessed as activation of Nrf2 signaling pathway measured after 18 hrs by steady-Glo luciferase assay | ec50 | 0.0070 | uM |
| N-[4-[2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl(2H-tetrazol-5-ylmethyl)amino]naphthalen-1-yl]-N-(2H-tetrazol-5-ylmethyl)-2,3-dihydro-1,4-benzodioxine-6-sulfonamide | 1755203: Inhibition of recombinant human KEAP1 Kelch domain (321 to 609 residues) expressed in Escherichia coli BL21 (DE3)pLysS cells interaction with FITC-9mer Nrf2 (unknown origin) incubated for 30 mins under shaking condition by TR-FRET assay | ic50 | 0.0072 | uM |
| 3-[(4S,7S,11S,13S,16S,19S,25S,28S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-28-carbamoyl-16-(2-carboxyethyl)-7-(carboxymethyl)-11-fluoro-19-[(1R)-1-hydroxyethyl]-5,8,14,17,20,23,26-heptaoxo-1,6,9,15,18,21,24,27,31,32-decazatricyclo[28.2.1.09,13]tritriaconta-30(33),31-dien-25-yl]propanoic acid | 1677710: Binding affinity to human KEAP1 Kelch domain (322 to 609 residues) incubated for 60 mins by TR-FRET assay | ic50 | 0.0074 | uM |
| 3-[(3S,6S,12S,15S,21S,24S,27S,29S)-6-[[(2S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-5-carbamimidamido-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-carbamoylpyrrolidine-1-carbonyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]pentanoyl]amino]acetyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-12-carbamoyl-24-(2-carboxyethyl)-3-(carboxymethyl)-29-fluoro-21-[(1R)-1-hydroxyethyl]-2,5,9,14,17,20,23,26-octaoxo-1,4,10,13,16,19,22,25-octazabicyclo[25.3.0]triacontan-15-yl]propanoic acid | 1677710: Binding affinity to human KEAP1 Kelch domain (322 to 609 residues) incubated for 60 mins by TR-FRET assay | ic50 | 0.0075 | uM |
| 3-[3-(difluoromethoxy)-5-fluoro-2-pyridinyl]-3-methoxy-5,5-dimethyl-6-oxocyclohexene-1-carbonitrile | 1511440: Inhibition of KEAP1 interaction with Nrf2 in human HEK293 cells transfected with ARE-LUC assessed as activation of Nrf2 signaling pathway measured after 18 hrs by steady-Glo luciferase assay | ec50 | 0.0080 | uM |
| 2-[[4-[carboxymethyl-[(6-chloro-2,3-dihydro-1,4-benzodioxin-7-yl)sulfonyl]amino]naphthalen-1-yl]-[(6-chloro-2,3-dihydro-1,4-benzodioxin-7-yl)sulfonyl]amino]acetic acid | 1755203: Inhibition of recombinant human KEAP1 Kelch domain (321 to 609 residues) expressed in Escherichia coli BL21 (DE3)pLysS cells interaction with FITC-9mer Nrf2 (unknown origin) incubated for 30 mins under shaking condition by TR-FRET assay | ic50 | 0.0089 | uM |
CTD chemical–gene interactions
193 total (human), top 30 by PubMed support.
| Chemical | Actions (top 5) | PubMed papers |
|---|---|---|
| Benzo(a)pyrene | decreases expression, increases expression | 7 |
| Hydrogen Peroxide | increases expression, affects reaction, affects binding, increases activity, decreases reaction (+3 more) | 7 |
| sulforaphane | increases metabolic processing, increases activity, increases expression, increases reaction, increases response to substance (+5 more) | 6 |
| sodium arsenite | increases reaction, decreases reaction, increases methylation, increases activity, affects localization (+4 more) | 6 |
| Arsenic Trioxide | affects reaction, increases expression, decreases expression, affects response to substance, decreases reaction (+4 more) | 6 |
| Cisplatin | affects cotreatment, increases expression, decreases stability, increases response to substance, affects reaction | 6 |
| (+)-JQ1 compound | decreases expression, increases reaction | 4 |
| Doxorubicin | decreases response to substance, increases expression, increases response to substance, decreases export | 4 |
| Oxygen | decreases reaction, increases degradation, increases expression, decreases expression, affects cotreatment | 4 |
| decabromobiphenyl ether | increases expression, decreases reaction, decreases expression | 3 |
| diethyl maleate | increases expression | 3 |
| 2-tert-butylhydroquinone | decreases reaction, increases ubiquitination, increases reaction, increases expression, increases activity (+2 more) | 3 |
| Resveratrol | affects cotreatment, decreases reaction, increases expression, affects binding, affects expression | 3 |
| Decitabine | increases expression, affects expression, affects methylation, decreases expression, decreases reaction (+1 more) | 3 |
| Ascorbic Acid | affects binding, affects cotreatment, decreases expression, decreases reaction, increases abundance (+1 more) | 3 |
| Curcumin | decreases expression, decreases reaction, increases ubiquitination, increases expression | 3 |
| Etoposide | increases response to substance, affects reaction, increases expression, decreases response to substance | 3 |
| Plant Extracts | decreases reaction, increases expression, decreases expression, increases chemical synthesis, affects cotreatment | 3 |
| Quercetin | decreases expression, decreases reaction, increases abundance, increases expression, increases degradation (+1 more) | 3 |
| Valproic Acid | affects expression, decreases expression | 3 |
| Cadmium Chloride | decreases expression, increases abundance, decreases reaction | 3 |
| triptolide | decreases expression | 2 |
| arsenite | affects response to substance, decreases reaction, decreases expression, increases expression, increases reaction (+1 more) | 2 |
| solanesol | decreases reaction, increases expression, affects binding | 2 |
| brusatol | increases expression, decreases expression, decreases response to substance, decreases reaction | 2 |
| andrographolide | decreases expression | 2 |
| mercuric bromide | increases expression, affects cotreatment | 2 |
| epigallocatechin gallate | increases expression, increases reaction | 2 |
| bardoxolone methyl | decreases expression, increases expression | 2 |
| Rosiglitazone | increases reaction, increases response to substance, increases expression | 2 |
ChEMBL screening assays
537 unique, capped per target: 535 binding, 1 functional, 1 admet
Representative assays (with source publication via chembl_document):
| Assay ID | Type | Description | Source paper |
|---|---|---|---|
| CHEMBL2072790 | Binding | Inhibition of Keap1 interaction with Nrf2 in human THP1 cells assessed as increase in HO-1 mRNA expression at 100 uM from 3 to 6 hrs by qRT-PCR analysis | Anti-inflammatory Effect of a Cell-Penetrating Peptide Targeting the Nrf2/Keap1 Interaction. — ACS Med Chem Lett |
| CHEMBL2114882 | Functional | PubChem BioAssay. Thermal shift assay to identify compound binding to Kelch domain of Keap1 protein Measured in Biochemical System Using RT-PCR - 2119-02_Inhibitor_Dose_CherryPick_Activity. (Class of assay: confirmatory) | PubChem BioAssay data set |
| CHEMBL4140689 | ADMET | Activation of keap1 in human TIG3 cells assessed as Nrf2 nuclear accumulation at 0.6 uM by immuno staining analysis | 2,3-Dihydro-3β-methoxy Withaferin-A Protects Normal Cells against Stress: Molecular Evidence of Its Potent Cytoprotective Activity. — J Nat Prod |
Cellosaurus cell lines
25 cell lines: 23 cancer cell line, 1 transformed cell line, 1 embryonic stem cell
First 10 cell lines (id-ordered, not curated):
| Cellosaurus | Name | Category | Sex |
|---|---|---|---|
| CVCL_1537 | NCI-H2172 | Cancer cell line | Female |
| CVCL_4972 | MHCC97-H | Cancer cell line | Male |
| CVCL_6832 | HCCLM3 | Cancer cell line | Male |
| CVCL_7680 | HCCLM6 | Cancer cell line | Male |
| CVCL_A5CU | HCCLM9 | Cancer cell line | Male |
| CVCL_A9LY | MHCC97H-GFP-LC3 | Cancer cell line | Male |
| CVCL_B8J9 | Abcam HCT 116 KEAP1 KO | Cancer cell line | Male |
| CVCL_B8Y3 | Abcam MCF-7 KEAP1 KO | Cancer cell line | Female |
| CVCL_B9LJ | Abcam A-549 KEAP1 KO | Cancer cell line | Male |
| CVCL_D1TC | Abcam U-87MG KEAP1 KO | Cancer cell line | Male |
Clinical trials (associated diseases)
2 trials via MONDO — disease-level, not drug-specific.
| Trial | Phase | Status | Title |
|---|---|---|---|
| NCT04411290 | Not specified | UNKNOWN | Malignancy Predictors, Bethesda and TI-RADS Scores Correlated With Final Histopathology in Thyroid Diseases |
| NCT05774535 | Not specified | WITHDRAWN | Prospective, Observational Study on the Carotid Intima-media Thickness in Patients Undergoing Thyroid Surgery |
Related Atlas pages
- Associated diseases: goiter, multinodular 1, with or without Sertoli-Leydig cell tumors
- Disease cohort memberships (association, not causation — diseases whose associated-gene cohort lists this gene; a subset are also under Associated diseases): goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, non-small cell lung carcinoma, sclerosing cholangitis