inhibitor of nuclear factor kappa B kinase subunit beta | IKK family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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inhibitor of nuclear factor kappa B kinase subunit beta

  Target has curated data in GtoImmuPdb

Target id: 2039

Nomenclature: inhibitor of nuclear factor kappa B kinase subunit beta

Abbreviated Name: IKK-beta

Family: IKK family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 756 8p11.2 IKBKB inhibitor of nuclear factor kappa B kinase subunit beta
Mouse - 757 8 A3-A4 Ikbkb inhibitor of kappaB kinase beta
Rat - 757 16 q12.5 Ikbkb inhibitor of nuclear factor kappa B kinase subunit beta
Previous and Unofficial Names
AIM-1 | I-kappa-B kinase 2 | I-kappa-B-kinase beta | IKK2 | IKKB | inhibitor of kappa light polypeptide gene enhancer in B-cells | inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta
Database Links
BRENDA
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  NEMO/IKKb association domain structure
PDB Id:  3BRV
Resolution:  2.2Å
Species:  Human
References:  12
Enzyme Reaction
EC Number: 2.7.11.10

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

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 47 [PMID: 28737909] Hs Inhibition 5.6 pKi 2
pKi 5.6 (Ki 2.3x10-6 M) [2]
IKK-beta inhibitor R-28 Hs Inhibition 8.1 pIC50 9
pIC50 8.1 (IC50 7.94x10-9 M) [9]
IKK-2 inhibitor IV Hs Inhibition 7.8 pIC50 11
pIC50 7.8 (IC50 1.79x10-8 M) [11]
Description: FRET measurement using recombinant human IKK2 (residues 1-756)
BI605906 Hs Inhibition 7.6 pIC50 8
pIC50 7.6 (IC50 2.6x10-8 M) [8]
PHA-408 Hs Inhibition 7.4 pIC50 10
pIC50 7.4 (IC50 4x10-8 M) [10]
MLN-120B Hs Inhibition 7.2 pIC50 14
pIC50 7.2 (IC50 6x10-8 M) [14]
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BMS-345541 Hs Negative 6.9 pKd 6
pKd 6.9 (Kd 1.3x10-7 M) [6]
BMS-345541 Hs Negative 6.5 pIC50 5
pIC50 6.5 (IC50 3x10-7 M) [5]
DiscoveRx KINOMEscan® screen
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: 6,15

Key to terms and symbols Click column headers to sort
Target used in screen: IKK-beta
Ligand Sp. Type Action Value Parameter
lestaurtinib Hs Inhibitor Inhibition 7.9 pKd
MLN-120B Hs Inhibitor Inhibition 7.7 pKd
staurosporine Hs Inhibitor Inhibition 7.5 pKd
tamatinib Hs Inhibitor Inhibition 7.2 pKd
AST-487 Hs Inhibitor Inhibition 7.0 pKd
BMS-345541 Hs Inhibitor Inhibition 6.9 pKd
fedratinib Hs Inhibitor Inhibition 6.4 pKd
KW-2449 Hs Inhibitor Inhibition 6.4 pKd
ruxolitinib Hs Inhibitor Inhibition 5.6 pKd
SB203580 Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
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: 1,7

Key to terms and symbols Click column headers to sort
Target used in screen: IKKβ/IKKb(IKBKB)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
IKK-2 inhibitor IV Hs Inhibitor Inhibition 9.0 12.0 8.0
K-252a Hs Inhibitor Inhibition 38.8 17.0 3.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 49.3 33.0 6.0
JAK inhibitor I Hs Inhibitor Inhibition 52.1 42.0 27.0
staurosporine Hs Inhibitor Inhibition 53.4 38.5 12.0
JAK3 inhibitor VI Hs Inhibitor Inhibition 69.2 51.0 22.0
GSK-3 inhibitor XIII Hs Inhibitor Inhibition 69.8 78.0 51.0
PKR inhibitor Hs Inhibitor Inhibition 70.2 68.0 25.0
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 73.4 111.0 81.0
SP600125 Hs Inhibitor Inhibition 75.8 78.0 43.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Iκβ kinase β (IKK-2) is the pivotal enzyme component of the Iκβ kinase (IKK) complex, a complex crucial in regulating expression and activation of inflammatory mediators in airway epithelium. IKK-2 is an attractive target for development of pharmaceutical inhibitors with antiinflammatory action as treatments for asthma and chronic obstructive pulmonary disease (COPD) [3-4,13].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 5 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0006954 inflammatory response TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
GO:0045087 innate immune response TAS
Immuno Process:  Antigen presentation
GO Annotations:  Associated to 1 GO processes
GO:0002479 antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 5 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0050852 T cell receptor signaling pathway TAS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 4 GO processes
GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway TAS
GO:0033209 tumor necrosis factor-mediated signaling pathway IMP
GO:0070498 interleukin-1-mediated signaling pathway IMP
GO:0071356 cellular response to tumor necrosis factor IDA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 5 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0050852 T cell receptor signaling pathway TAS
Clinically-Relevant Mutations and Pathophysiology
Disease:  Immunodeficiency 15; IMD15
Synonyms: Severe combined immunodeficiency due to IKK2 deficiency [Orphanet: ORPHA397787]
OMIM: 615592
Orphanet: ORPHA397787

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. Baxter A, Brough S, Cooper A, Floettmann E, Foster S, Harding C, Kettle J, McInally T, Martin C, Mobbs M et al.. (2004) Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors. Bioorg. Med. Chem. Lett., 14 (11): 2817-22. [PMID:15125939]

4. Birrell MA, Hardaker E, Wong S, McCluskie K, Catley M, De Alba J, Newton R, Haj-Yahia S, Pun KT, Watts CJ et al.. (2005) Ikappa-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma. Am. J. Respir. Crit. Care Med., 172 (8): 962-71. [PMID:16002568]

5. 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]

6. 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]

7. 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]

8. Ginn J, Sorcek R, Turner M, Young E. (2007) Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses. Patent number: US20070293533. Assignee: Ginn JD, Sorcek RJ, Turner MR, Young ERR. Priority date: 06/06/2006. Publication date: 20/12/2007.

9. Kerns JK, Busch-Petersen J, Fu W, Boehm JC, Nie H, Muratore M, Bullion A, Lin G, Davis R, Lin X et al.. (2018) 3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent. ACS Medicinal Chemistry Letters, Articles ASAP. DOI: 10.1021/acsmedchemlett.8b00291

10. 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]

11. Podolin PL, Callahan JF, Bolognese BJ, Li YH, Carlson K, Davis TG, Mellor GW, Evans C, Roshak AK. (2005) Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB Kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell Proliferation. J. Pharmacol. Exp. Ther., 312 (1): 373-81. [PMID:15316093]

12. Rushe M, Silvian L, Bixler S, Chen LL, Cheung A, Bowes S, Cuervo H, Berkowitz S, Zheng T, Guckian K et al.. (2008) Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site. Structure, 16 (5): 798-808. [PMID:18462684]

13. Sommers CD, Thompson JM, Guzova JA, Bonar SL, Rader RK, Mathialagan S, Venkatraman N, Holway VW, Kahn LE, Hu G et al.. (2009) Novel tight-binding inhibitory factor-kappaB kinase (IKK-2) inhibitors demonstrate target-specific anti-inflammatory activities in cellular assays and following oral and local delivery in an in vivo model of airway inflammation. J. Pharmacol. Exp. Ther., 330 (2): 377-88. [PMID:19478133]

14. Wen D, Nong Y, Morgan JG, Gangurde P, Bielecki A, Dasilva J, Keaveney M, Cheng H, Fraser C, Schopf L et al.. (2006) A selective small molecule IkappaB Kinase beta inhibitor blocks nuclear factor kappaB-mediated inflammatory responses in human fibroblast-like synoviocytes, chondrocytes, and mast cells. J. Pharmacol. Exp. Ther., 317 (3): 989-1001. [PMID:16525037]

15. 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: inhibitor of nuclear factor kappa B kinase subunit beta. Last modified on 14/11/2018. Accessed on 16/09/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2039.