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kelch like ECH-associated protein 1

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Target id: 2757

Nomenclature: kelch like ECH-associated protein 1

Family: Kelch-like proteins

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 624 19p13.2 KEAP1 kelch like ECH associated protein 1
Mouse - 624 9 A3 Keap1 kelch-like ECH-associated protein 1
Rat - 624 8q13 Keap1 Kelch-like ECH-associated protein 1
Previous and Unofficial Names Click here for help
INrf2 | kelch-like ECH-associated protein 1
Database Links Click here for help
Alphafold Q14145 (Hs), Q9Z2X8 (Mm), P57790 (Rn)
CATH/Gene3D 2.130.10.80, 2.120.10.80
ChEMBL Target CHEMBL2069156 (Hs), CHEMBL3562164 (Mm), CHEMBL4523596 (Rn)
DrugBank Target Q14145 (Hs)
Ensembl Gene ENSG00000079999 (Hs), ENSMUSG00000003308 (Mm), ENSRNOG00000020878 (Rn)
Entrez Gene 9817 (Hs), 50868 (Mm), 117519 (Rn)
Human Protein Atlas ENSG00000079999 (Hs)
KEGG Gene hsa:9817 (Hs), mmu:50868 (Mm), rno:117519 (Rn)
OMIM 606016 (Hs)
Pharos Q14145 (Hs)
RefSeq Nucleotide NM_012289 (Hs), NM_016679 (Mm), NM_057152 (Rn)
RefSeq Protein NP_036421 (Hs), NP_057888 (Mm), NP_476493 (Rn)
UniProtKB Q14145 (Hs), Q9Z2X8 (Mm), P57790 (Rn)
Wikipedia KEAP1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of murine Keap1 in complex with RA839, a non-covalent small-molecule binder to Keap1 and selective activator of Nrf2 signalling.
PDB Id:  5CGJ
Ligand:  RA839
Resolution:  3.36Å
Species:  Mouse
References:  13

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
biKEAP1 Small molecule or natural product Hs Binding 8.1 pIC50 5
⤷ pIC50 8.1 (IC50 8.49x10-9 M) [5]
Description: Determined in a fluorescence polarization (FP) assay, measuring displacement of a NRF2 ETGE motif derived peptide from KEAP1 Kelch domain
Nrf2 peptide [PMID: 23647822] Peptide Primary target of this compound Hs Binding 7.5 pIC50 7
⤷ pIC50 7.5 (IC50 3.3x10-8 M) [7]
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CPUY192018 Small molecule or natural product Immunopharmacology Ligand Hs Binding 7.4 – 8.4 pKd 3,6
⤷ pKd 8.4 (Kd 3.59x10-9 M) [3]
Description: Binding to hKEAP1 in a biolayer interferometry assay.
pKd 7.4 (Kd 3.98x10-8 M) [6]
Description: Measuerd using a isothermal titration calorimetry (ITC) assay.
compound 10 [PMID: 31411465] Small molecule or natural product Immunopharmacology Ligand Hs Binding 7.7 pKd 11
⤷ pKd 7.7 (Kd 1.9x10-8 M) [11]
Description: Binding affinity determined by surface plasmon resonance.
isoquinoline 17 [PMID: 30122040] Small molecule or natural product Hs Binding 7.0 pKd 8
⤷ pKd 7.0 (Kd 1.02x10-7 M) [8]
Description: Binding to hKEAP1 by SPR.
RA839 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Binding 5.2 pKd 13
⤷ pKd 5.2 (Kd 6x10-6 M) [13]
Description: Binding affinity determined by ITC, between KEAP1 kelch domain and RA839.
CPUY192018 Small molecule or natural product Immunopharmacology Ligand Hs Binding 7.5 pEC50 3
⤷ pEC50 7.5 (EC50 2.86x10-8 M) [3]
Description: Value determined using a fluorescence polarization competition assay.
CPUY192018 Small molecule or natural product Immunopharmacology Ligand Hs Binding 7.8 pIC50 4
⤷ pIC50 7.8 (IC50 1.44x10-8 M) [4]
Description: Measured using a fluorescence polarisation assay.
isoquinoline 17 [PMID: 30122040] Small molecule or natural product Hs Binding 7.2 pIC50 8
⤷ pIC50 7.2 (IC50 6x10-8 M) [8]
Description: Measured by fluorescence anisotropy.
bardoxolone Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Binding >7.0 pIC50 1
⤷ pIC50 >7.0 (IC50 <1x10-7 M) [1]
Description: Measuring inhibition of KEAP1 binding to Cul3 using an AlphaScreen bead-based proximity assay.
RA839 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Binding ~6.8 pIC50 13
⤷ pIC50 ~6.8 (IC50 ~1.4x10-7 M) [13]
Description: Inhibition constant determined using fluorescence polarization to monitor the interaction of human KEAP1 kelch domain (amino acids Ala321–Thr609) to a fluorescently labeled human Nrf2 peptide (Alexa633-AFFAQLQLDEETGEFL).
Immunopharmacology Comments
Transcription of many important detoxification enzymes is regulated by the Nrf2 transcription factor, which is (negatively) regulated by interaction with KEAP1, and when activated by disengagement from KEAP1, enters the nucleus and binds genes with an antioxidant responsive element (ARE) in their promoter sequences. Nrf2-responsive genes play important roles in the cellular defense system, in the regulation of the response to oxidative stress, and facilitate detoxification, antioxidant, cytoprotective and anti-inflammatory functions. Small molecule drug-like compounds that inhibit the KEAP1-Nrf2 protein-protein interaction (a.k.a. Nrf2 activators) are being developed for their potential anti-inflammatory action. The approved MS prodrug dimethyl fumarate was reported to exploit this molecular mechanism, although more recent evidence suggests that its effects may be Nrf2 independent [10]. In order to examine the veracity of Nrf2 activation as an anti-inflammatory modality further, non-electrophilic KEAP1 binding, Nrf2-activating compounds are being developed with the goal of improving on-target selectivity [2-3,9].
Immuno Process Associations
Immuno Process:  Cellular signalling
Immuno Process:  Cytokine production & signalling
General Comments
The KEAP1 protein homodimerises and acts as a substrate-recognition adaptor in the formation of the Cullin-RING ligase (CRL) 3 E3 ubiquitin ligase complex. The KEAP1 homodimer substrate is the transcription factor Nrf2 (NF-E2-related factor 2; NFE2L2; Q16236), a master regulator of the antioxidant response. KEAP1 behaves as a repressor that negatively regulates Nrf2 transcriptional activity, by promoting Nrf2 ubiquitination and proteasomal degradation. Direct inhibition of the KEAP1-Nrf2 protein-protein interaction functionally activates transcription of Nrf2 regulated genes and this mechanism is considered a promising strategy for the development of novel drugs with potential antioxidant, anti-inflammatory, and anticancer activities [12].

References

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1. Cleasby A, Yon J, Day PJ, Richardson C, Tickle IJ, Williams PA, Callahan JF, Carr R, Concha N, Kerns JK et al.. (2014) Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS ONE, 9 (6): e98896. [PMID:24896564]

2. Jain AD, Potteti H, Richardson BG, Kingsley L, Luciano JP, Ryuzoji AF, Lee H, Krunic A, Mesecar AD, Reddy SP et al.. (2015) Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators. Eur J Med Chem, 103: 252-68. [PMID:26363505]

3. Jiang ZY, Lu MC, Xu LL, Yang TT, Xi MY, Xu XL, Guo XK, Zhang XJ, You QD, Sun HP. (2014) Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem, 57 (6): 2736-45. [PMID:24512214]

4. Jiang ZY, Xu LL, Lu MC, Chen ZY, Yuan ZW, Xu XL, Guo XK, Zhang XJ, Sun HP, You QD. (2015) Structure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction Inhibitor. J Med Chem, 58 (16): 6410-21. [PMID:26258437]

5. Lu M, Ji J, Lv Y, Zhao J, Liu Y, Jiao Q, Liu T, Mou Y, You Q, Jiang Z. (2023) Bivalent inhibitors of the BTB E3 ligase KEAP1 enable instant NRF2 activation to suppress acute inflammatory response. Cell Chem Biol, [Epub ahead of print]. [PMID:38157852]

6. Lu MC, Ji JA, Jiang YL, Chen ZY, Yuan ZW, You QD, Jiang ZY. (2016) An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis. Sci Rep, 6: 26585. [PMID:27215610]

7. Marcotte D, Zeng W, Hus JC, McKenzie A, Hession C, Jin P, Bergeron C, Lugovskoy A, Enyedy I, Cuervo H et al.. (2013) Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg Med Chem, 21 (14): 4011-9. [PMID:23647822]

8. Richardson BG, Jain AD, Potteti HR, Lazzara PR, David BP, Tamatam CR, Choma E, Skowron K, Dye K, Siddiqui Z et al.. (2018) Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors. J Med Chem, 61 (17): 8029-8047. [PMID:30122040]

9. Richardson BG, Jain AD, Speltz TE, Moore TW. (2015) Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway. Bioorg Med Chem Lett, 25 (11): 2261-8. [PMID:25937010]

10. Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, Spencer CM, Shetty A, Sagan SA, Cree BA, Sobel RA, Wipke BT, Steinman L et al.. (2016) Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proc Natl Acad Sci USA, 113 (17): 4777-82. [PMID:27078105]

11. Tran KT, Pallesen JS, Solbak SMØ, Narayanan D, Baig A, Zang J, Aguayo-Orozco A, Carmona RMC, Garcia AD, Bach A. (2019) A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity. J Med Chem, 62 (17): 8028-8052. [PMID:31411465]

12. Wells G. (2015) Peptide and small molecule inhibitors of the Keap1-Nrf2 protein-protein interaction. Biochem Soc Trans, 43 (4): 674-9. [PMID:26551711]

13. Winkel AF, Engel CK, Margerie D, Kannt A, Szillat H, Glombik H, Kallus C, Ruf S, Güssregen S, Riedel J et al.. (2015) Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling. J Biol Chem, 290 (47): 28446-55. [PMID:26459563]

How to cite this page

Kelch-like proteins: kelch like ECH-associated protein 1. Last modified on 04/01/2024. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2757.