kelch like ECH-associated protein 1 | Kelch-like proteins | IUPHAR/BPS Guide to PHARMACOLOGY

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kelch like ECH-associated protein 1

target has curated data in GtoImmuPdb

Target id: 2757

Nomenclature: kelch like ECH-associated protein 1

Family: Kelch-like proteins

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
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 - 620 8q13 Keap1 Kelch-like ECH-associated protein 1
Previous and Unofficial Names
INrf2 | kelch-like ECH-associated protein 1
Database Links
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
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:  12

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
Nrf2 peptide [PMID: 23647822] Hs Binding 7.5 pIC50 6
pIC50 7.5 (IC50 3.3x10-8 M) [6]
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CPUY192018 Hs Binding 7.4 – 8.4 pKd 3,5
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) [5]
Description: Measuerd using a isothermal titration calorimetry (ITC) assay.
compound 10 [PMID: 31411465] Hs Binding 7.7 pKd 10
pKd 7.7 (Kd 1.9x10-8 M) [10]
Description: Binding affinity determined by surface plasmon resonance.
isoquinoline 17 [PMID: 30122040] Hs Binding 7.0 pKd 7
pKd 7.0 (Kd 1.02x10-7 M) [7]
Description: Binding to hKEAP1 by SPR.
RA839 Hs Binding 5.2 pKd 12
pKd 5.2 (Kd 6x10-6 M) [12]
Description: Binding affinity determined by ITC, between KEAP1 kelch domain and RA839.
CPUY192018 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 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] Hs Binding 7.2 pIC50 7
pIC50 7.2 (IC50 6x10-8 M) [7]
Description: Measured by fluorescence anisotropy.
bardoxolone 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 Hs Binding ~6.8 pIC50 12
pIC50 ~6.8 (IC50 ~1.4x10-7 M) [12]
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 [9]. 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 [2-3,8].
Immuno Process Associations
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0016567 protein ubiquitination IDA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0071353 cellular response to interleukin-4 IEA
General Comments
The KEAP1 protein binds to and negatively regulates the transcriptional activity of NF-E2-related factor 2 (Nrf2; NFE2L2; Q16236). Nrf2 is recognised as a master regulator of the antioxidant response. KEAP1 achieves inhibition of Nrf2 transactivation capacity by mediating Nrf2 ubiquitination and subsequent degradation. Direct inhibition of the KEAP1-Nrf2 protein-protein interaction has emerged as a promising strategy that is being exploited for the development of novel drugs with potential antioxidant, antiinflammatory, and anticancer activities [11].

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 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]

6. 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]

7. 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]

8. 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]

9. 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. U.S.A., 113 (17): 4777-82. [PMID:27078105]

10. 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., [Epub ahead of print]. [PMID:31411465]

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

12. 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 11/09/2019. Accessed on 19/09/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2757.