inhibitor of nuclear factor kappa B kinase subunit epsilon | IKK family | IUPHAR/BPS Guide to PHARMACOLOGY

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inhibitor of nuclear factor kappa B kinase subunit epsilon

target has curated data in GtoImmuPdb

Target id: 2040

Nomenclature: inhibitor of nuclear factor kappa B kinase subunit epsilon

Abbreviated Name: IKK-epsilon

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 - 716 1q31 IKBKE inhibitor of nuclear factor kappa B kinase subunit epsilon
Mouse - 717 1 E4 Ikbke inhibitor of kappaB kinase epsilon
Rat - 717 13 q13 Ikbke inhibitor of nuclear factor kappa B kinase subunit epsilon
Previous and Unofficial Names
IKKE | IKKepsilon | IKKI | Inducible I kappa-B kinase | inhibitor of kappa light polypeptide gene enhancer in B-cells | inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
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
GSK8612 Hs Inhibition ~6.1 pKd 11
pKd ~6.1 (Kd ~8x10-7 M) [11]
Description: In a Kinobeads assay using lysates from HEK293/K-562/Placenta/HepG2 cells.
SR8185 Hs Inhibition 8.5 pIC50 5
pIC50 8.5 (IC50 3x10-9 M) [5]
Description: In an enzyme assay.
MPI-0485520 Hs Inhibition 8.5 pIC50 8
pIC50 8.5 (IC50 3x10-9 M) [8]
Description: Using a Kinase Hotspot® assay.
compound 17d [PMID: 23099093] Hs Inhibition 7.5 pIC50 6
pIC50 7.5 (IC50 3x10-8 M) [6]
compound II [PMID: 21329883] Hs Inhibition 7.2 pIC50 7
pIC50 7.2 (IC50 5.9x10-8 M) [7]
Description: In a biochemical assay using purified recombinant enzyme.
MRT67307 Hs Inhibition 6.8 pIC50 2
pIC50 6.8 (IC50 1.6x10-7 M) [2]
amlexanox Hs Inhibition 5.7 – 6.0 pIC50 9
pIC50 5.7 – 6.0 (IC50 2x10-6 – 1x10-6 M) [9]
Description: Inhibition of substrate phosphorylation.
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: 3,12

Key to terms and symbols Click column headers to sort
Target used in screen: IKK-epsilon
Ligand Sp. Type Action Value Parameter
staurosporine Hs Inhibitor Inhibition 8.3 pKd
lestaurtinib Hs Inhibitor Inhibition 8.0 pKd
tamatinib Hs Inhibitor Inhibition 7.9 pKd
bosutinib Hs Inhibitor Inhibition 7.3 pKd
midostaurin Hs Inhibitor Inhibition 6.8 pKd
KW-2449 Hs Inhibitor Inhibition 6.5 pKd
fedratinib Hs Inhibitor Inhibition 6.4 pKd
dovitinib Hs Inhibitor Inhibition 6.3 pKd
SU-14813 Hs Inhibitor Inhibition 6.3 pKd
sunitinib Hs Inhibitor Inhibition 6.2 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

Key to terms and symbols Click column headers to sort
Target used in screen: nd/IKKe(IKBKE)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 0.3
K-252a Hs Inhibitor Inhibition 2.4
midostaurin Hs Inhibitor Inhibition 9.9
JAK3 inhibitor VI Hs Inhibitor Inhibition 14.9
Syk inhibitor Hs Inhibitor Inhibition 21.9
SB 218078 Hs Inhibitor Inhibition 23.9
JAK inhibitor I Hs Inhibitor Inhibition 25.4
PKR inhibitor Hs Inhibitor Inhibition 27.6
SU11652 Hs Inhibitor Inhibition 29.4
dovitinib Hs Inhibitor Inhibition 42.9
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
IKKε is the only inducible IKK family member. Expression is induced in response to LPS, viral infection and several cytokines. IKKε expression is restricted to pancreas, thymus, spleen and peripheral blood leukocytes. This is in contrast to all other IKK family kinases which are constitutively and ubiquitously expressed.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 3 GO processes
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
click arrow to show/hide IEA associations
GO:0034340 response to type I interferon IEA
GO:0060340 positive regulation of type I interferon-mediated signaling pathway IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 2 GO processes
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
click arrow to show/hide IEA associations
GO:0060340 positive regulation of type I interferon-mediated signaling pathway IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 4 GO processes
GO:0032480 negative regulation of type I interferon production TAS
GO:0035456 response to interferon-beta IMP
click arrow to show/hide IEA associations
GO:0034340 response to type I interferon IEA
GO:0060340 positive regulation of type I interferon-mediated signaling pathway IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
General Comments
IKKε and TBK1 phosphorylate the transcription factors interferon (IFN) regulator factor (IRF) 3 and 7. This function is critical for the induction of the type I IFN response (induction of IFN genes and IFN-stimulated genes) in response to microbial infection [4,10].

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. Clark K, Peggie M, Plater L, Sorcek RJ, Young ER, Madwed JB, Hough J, McIver EG, Cohen P. (2011) Novel cross-talk within the IKK family controls innate immunity. Biochem. J., 434 (1): 93-104. [PMID:21138416]

3. 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]

4. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T. (2003) IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol., 4 (5): 491-6. [PMID:12692549]

5. Li J, Huang J, Jeong JH, Park SJ, Wei R, Peng J, Luo Z, Chen YT, Feng Y, Luo JL. (2014) Selective TBK1/IKKi dual inhibitors with anticancer potency. Int. J. Cancer, 134 (8): 1972-80. [PMID:24150799]

6. McIver EG, Bryans J, Birchall K, Chugh J, Drake T, Lewis SJ, Osborne J, Smiljanic-Hurley E, Tsang W, Kamal A et al.. (2012) Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases. Bioorg. Med. Chem. Lett., 22 (23): 7169-73. [PMID:23099093]

7. Ou YH, Torres M, Ram R, Formstecher E, Roland C, Cheng T, Brekken R, Wurz R, Tasker A, Polverino T et al.. (2011) TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation. Mol. Cell, 41 (4): 458-70. [PMID:21329883]

8. Perrior TR, Newton GK, Stewart MR, Aqil R. (2012) Pyrimidine compounds as inhibitors of protein kinases ikk epsilon and/or tbk-1, processes for their preparation, and pharmaceutical compositions containing them. Patent number: WO2012010826. Assignee: Domainex Limited. Priority date: 19/07/2010. Publication date: 26/01/2012.

9. Reilly SM, Chiang SH, Decker SJ, Chang L, Uhm M, Larsen MJ, Rubin JR, Mowers J, White NM, Hochberg I et al.. (2013) An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice. Nat. Med., 19 (3): 313-21. [PMID:23396211]

10. Sankar S, Chan H, Romanow WJ, Li J, Bates RJ. (2006) IKK-i signals through IRF3 and NFkappaB to mediate the production of inflammatory cytokines. Cell. Signal., 18 (7): 982-93. [PMID:16199137]

11. Thomson DW, Poeckel D, Zinn N, Rau C, Strohmer K, Wagner AJ, Graves AP, Perrin J, Bantscheff M, Duempelfeld B et al.. (2019) Discovery of GSK8612, a Highly Selective and Potent TBK1 Inhibitor. ACS Medicinal Chemistry Letters, Article ASAP. DOI: 10.1021/acsmedchemlett.9b00027

12. 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 epsilon. Last modified on 21/03/2019. Accessed on 05/12/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2040.