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inhibitor of nuclear factor kappa B kinase subunit epsilon

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Target id: 2040

Nomenclature: inhibitor of nuclear factor kappa B kinase subunit epsilon

Abbreviated Name: IKK-epsilon

Family: IKK family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 716 1q32.1 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 Click here for help
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 Click here for help
Alphafold Q14164 (Hs), Q9R0T8 (Mm)
BRENDA 2.7.11.10
ChEMBL Target CHEMBL3529 (Hs)
Ensembl Gene ENSG00000263528 (Hs), ENSMUSG00000042349 (Mm), ENSRNOG00000025100 (Rn)
Entrez Gene 9641 (Hs), 56489 (Mm), 363984 (Rn)
Human Protein Atlas ENSG00000263528 (Hs)
KEGG Enzyme 2.7.11.10
KEGG Gene hsa:9641 (Hs), mmu:56489 (Mm), rno:363984 (Rn)
OMIM 605048 (Hs)
Pharos Q14164 (Hs)
RefSeq Nucleotide NM_001193321 (Hs), NM_019777 (Mm), NM_001108854 (Rn)
RefSeq Protein NP_054721 (Hs), NP_062751 (Mm), NP_001102324 (Rn)
UniProtKB Q14164 (Hs), Q9R0T8 (Mm)
Wikipedia IKBKE (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
GSK8612 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition ~6.1 pKd 13
⤷ pKd ~6.1 (Kd ~8x10-7 M) [13]
Description: In a Kinobeads assay using lysates from HEK293/K-562/Placenta/HepG2 cells.
BAY-985 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.7 pIC50 6
⤷ pIC50 8.7 (IC50 2x10-9 M) [6]
SR8185 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.5 pIC50 7
⤷ pIC50 8.5 (IC50 3x10-9 M) [7]
Description: In an enzyme assay.
MPI-0485520 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.5 pIC50 10
⤷ pIC50 8.5 (IC50 3x10-9 M) [10]
Description: Using a Kinase Hotspot® assay.
compound 17d [PMID: 23099093] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 8
⤷ pIC50 7.5 (IC50 3x10-8 M) [8]
BX-795 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.4 pIC50 3
⤷ pIC50 7.4 (IC50 4.1x10-8 M) [3]
compound II [PMID: 21329883] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 9
⤷ pIC50 7.2 (IC50 5.9x10-8 M) [9]
Description: In a biochemical assay using purified recombinant enzyme.
MRT67307 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.8 pIC50 2
⤷ pIC50 6.8 (IC50 1.6x10-7 M) [2]
amlexanox Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 5.7 – 6.0 pIC50 11
⤷ pIC50 5.7 – 6.0 (IC50 2x10-6 – 1x10-6 M) [11]
Description: Inhibition of substrate phosphorylation.
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: 4,14
Key to terms and symbols Click column headers to sort
Target used in screen: IKK-epsilon
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.3 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.0 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.9 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.3 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.8 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.5 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 6.3 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 6.3 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure 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 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
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.3
K-252a Small molecule or natural product Hs Inhibitor Inhibition 2.4
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 9.9
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 14.9
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 21.9
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 23.9
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 25.4
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 27.6
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 29.4
dovitinib Small molecule or natural product 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
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
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 [5,12].

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. Clark K, Plater L, Peggie M, Cohen P. (2009) Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation. J Biol Chem, 284 (21): 14136-46. [PMID:19307177]

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. 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]

6. Lefranc J, Schulze VK, Hillig RC, Briem H, Prinz F, Mengel A, Heinrich T, Balint J, Rengachari S, Irlbacher H et al.. (2020) Discovery of BAY-985, a Highly Selective TBK1/IKKε Inhibitor. J Med Chem, 63 (2): 601-612. DOI: 10.1021/acs.jmedchem.9b01460 [PMID:31859507]

7. 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]

8. 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]

9. 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]

10. 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.

11. 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]

12. 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]

13. 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 Med Chem Lett, 10 (5): 780-785. DOI: 10.1021/acsmedchemlett.9b00027 [PMID:31097999]

14. 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 03/11/2022. Accessed on 15/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2040.