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component of inhibitor of nuclear factor kappa B kinase complex

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Target id: 1989

Nomenclature: component of inhibitor of nuclear factor kappa B kinase complex

Abbreviated Name: IKK-alpha

Family: IKK family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 745 10q24.31 CHUK component of inhibitor of nuclear factor kappa B kinase complex
Mouse - 745 19 36.71 cM Chuk conserved helix-loop-helix ubiquitous kinase
Rat - 745 1 q54 Chuk component of inhibitor of nuclear factor kappa B kinase complex
Previous and Unofficial Names Click here for help
Chuk1 | conserved helix-loop-helix ubiquitous kinase | I-kappa-B kinase 1 | IkappaB kinase alpha | IkBKA | IKK1 | IKKA | IKKalpha | inhibitor of nuclear factor kappa-B kinase subunit alpha | NFKBIKA | nuclear factor NF-kappa-B inhibitor kinase alpha | TCF16
Database Links Click here for help
Alphafold O15111 (Hs), Q60680 (Mm)
BRENDA 2.7.11.10
ChEMBL Target CHEMBL3476 (Hs), CHEMBL5380 (Mm)
Ensembl Gene ENSG00000213341 (Hs), ENSMUSG00000025199 (Mm), ENSRNOG00000022485 (Rn)
Entrez Gene 1147 (Hs), 12675 (Mm), 309361 (Rn)
Human Protein Atlas ENSG00000213341 (Hs)
KEGG Enzyme 2.7.11.10
KEGG Gene hsa:1147 (Hs), mmu:12675 (Mm), rno:309361 (Rn)
OMIM 600664 (Hs)
Pharos O15111 (Hs)
RefSeq Nucleotide NM_001278 (Hs), NM_001162410 (Mm), NM_001107588 (Rn)
RefSeq Protein NP_001269 (Hs), NP_001155882 (Mm), NP_001101058 (Rn)
UniProtKB O15111 (Hs), Q60680 (Mm)
Wikipedia CHUK (Hs)
Enzyme Reaction Click here for help
EC Number: 2.7.11.10

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
BAY 61-3606 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.3 pKi 6
⤷ pKi 7.3 (Ki 4.5x10-8 M) [6]
compound 47 [PMID: 28737909] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.2 pKi 2
⤷ pKi 6.2 (Ki 6.5x10-7 M) [2]
PHA-408 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 4.8 pIC50 8
⤷ pIC50 4.8 (IC50 1.41x10-5 M) [8]
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BMS-345541 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Negative 5.4 pIC50 3
⤷ pIC50 5.4 (IC50 4x10-6 M) [3]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 4,9
Key to terms and symbols Click column headers to sort
Target used in screen: IKK-alpha
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.2 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.1 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 7.4 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.9 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.7 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 6.2 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.1 pKd
MLN-120B Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 6.0 pKd
PI-103 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.8 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,5
Key to terms and symbols Click column headers to sort
Target used in screen: IKKα/IKKA(CHUK)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Small molecule or natural product Hs Inhibitor Inhibition 36.5 2.0 3.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 40.3 5.5 1.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 53.2 8.0 1.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 54.4 10.0 1.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 60.3 5.0 0.0
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 72.0 90.0 86.0
aloisine A Small molecule or natural product Hs Inhibitor Inhibition 77.6 90.0 81.0
Cdk4 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 81.5 89.0 71.0
fascaplysin Small molecule or natural product Hs Inhibitor Inhibition 82.6 108.0 108.0
Flt-3 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 83.3 105.0 113.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Ikkα is one of the catalytic subunits of the IκB kinase (IKK) complex, an upstream component of the NF-κB signal transduction cascade; NF-κB signaling being involved in propagating the cellular response to inflammation. IKK frees NF-κB from its inhibitory interaction with IκBα (inhibitor of kappa B), allowing NF-κB translocation to the nucleus where it modulates transcriptional activity. Additional functions of Ikkα beyond NF-κB activation are reviewed in [7].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Antigen presentation
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Immuno Process:  Immune system development
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Cocoon syndrome
OMIM: 613630

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Anthony NG, Baiget J, Berretta G, Boyd M, Breen D, Edwards J, Gamble C, Gray AI, Harvey AL, Hatziieremia S et al.. (2017) Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers. J Med Chem, 60 (16): 7043-7066. [PMID:28737909]

3. Burke JR, Pattoli MA, Gregor KR, Brassil PJ, MacMaster JF, McIntyre KW, Yang X, Iotzova VS, Clarke W, Strnad J et al.. (2003) BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. J Biol Chem, 278 (3): 1450-6. [PMID:12403772]

4. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

5. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

6. Ho CM, Donovan-Banfield IZ, Tan L, Zhang T, Gray NS, Strang BL. (2016) Inhibition of IKKα by BAY61-3606 Reveals IKKα-Dependent Histone H3 Phosphorylation in Human Cytomegalovirus Infected Cells. PLoS ONE, 11 (3): e0150339. [PMID:26930276]

7. Huang WC, Hung MC. (2013) Beyond NF-κB activation: nuclear functions of IκB kinase α. J Biomed Sci, 20: 3. [PMID:23343355]

8. Mbalaviele G, Sommers CD, Bonar SL, Mathialagan S, Schindler JF, Guzova JA, Shaffer AF, Melton MA, Christine LJ, Tripp CS et al.. (2009) A novel, highly selective, tight binding IkappaB kinase-2 (IKK-2) inhibitor: a tool to correlate IKK-2 activity to the fate and functions of the components of the nuclear factor-kappaB pathway in arthritis-relevant cells and animal models. J Pharmacol Exp Ther, 329 (1): 14-25. [PMID:19168710]

9. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

How to cite this page

IKK family: component of inhibitor of nuclear factor kappa B kinase complex. Last modified on 27/03/2019. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1989.