TANK binding kinase 1 | IKK family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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TANK binding kinase 1

  Target has curated data in GtoImmuPdb

Target id: 2237

Nomenclature: TANK binding kinase 1

Abbreviated Name: TBK1

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 - 729 12q14.2 TBK1 TANK binding kinase 1
Mouse - 729 10 D2 Tbk1 TANK-binding kinase 1
Rat - 729 7 q22 Tbk1 TANK-binding kinase 1
Previous and Unofficial Names
NAK | TANK-binding kinase 1
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Structure of Tank-Binding Kinase 1 bound to MRT67307.
PDB Id:  4IM0
Resolution:  2.4Å
Species:  Human
References: 
Enzyme Reaction
EC Number: 2.7.11.1

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 ~8.0 pKd 21
pKd ~8.0 (Kd ~1x10-8 M) [21]
Description: In a Kinobeads assay using lysates from HEK293/K-562/Placenta/HepG2 cells.
MPI-0485520 Hs Inhibition 8.7 pIC50 17
pIC50 8.7 (IC50 2x10-9 M) [17]
Description: Using a Kinase Hotspot® assay.
AZ13102909 Hs Inhibition 8.3 pIC50 22
pIC50 8.3 (IC50 5x10-9 M) [22]
Description: In vitro biochemical assay.
compound 17d [PMID: 23099093] Hs Inhibition 8.2 pIC50 15
pIC50 8.2 (IC50 6x10-9 M) [15]
SR8185 Hs Inhibition >8.0 pIC50 14
pIC50 >8.0 (IC50 <1x10-8 M) [14]
Description: In an enzyme assay.
compound II [PMID: 21329883] Hs Inhibition 7.9 pIC50 16
pIC50 7.9 (IC50 1.3x10-8 M) [16]
Description: In a biochemical assay using purified recombinant enzyme.
MRT67307 Hs Inhibition 7.7 pIC50 4
pIC50 7.7 (IC50 1.9x10-8 M) [4]
amlexanox Hs Inhibition 5.7 – 6.0 pIC50 19
pIC50 5.7 – 6.0 (IC50 2x10-6 – 1x10-6 M) [19]
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: 6,24

Key to terms and symbols Click column headers to sort
Target used in screen: TBK1
Ligand Sp. Type Action Value Parameter
staurosporine Hs Inhibitor Inhibition 9.1 pKd
midostaurin Hs Inhibitor Inhibition 8.0 pKd
lestaurtinib Hs Inhibitor Inhibition 7.7 pKd
tamatinib Hs Inhibitor Inhibition 7.6 pKd
fedratinib Hs Inhibitor Inhibition 7.0 pKd
sunitinib Hs Inhibitor Inhibition 6.9 pKd
dovitinib Hs Inhibitor Inhibition 6.9 pKd
KW-2449 Hs Inhibitor Inhibition 6.9 pKd
SU-14813 Hs Inhibitor Inhibition 6.8 pKd
bosutinib Hs Inhibitor Inhibition 6.6 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: 1,9

Key to terms and symbols Click column headers to sort
Target used in screen: TBK1/TBK1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition -0.5 1.5 0.5
midostaurin Hs Inhibitor Inhibition 3.2 2.0 1.0
JAK3 inhibitor VI Hs Inhibitor Inhibition 4.4 1.0 0.0
K-252a Hs Inhibitor Inhibition 5.3 -1.0 3.0
SB 218078 Hs Inhibitor Inhibition 7.4 54.0 62.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 10.3 -1.0 -2.0
SU11652 Hs Inhibitor Inhibition 16.3 15.0 1.0
PKR inhibitor Hs Inhibitor Inhibition 18.8 7.0 0.0
STO609 Hs Inhibitor Inhibition 20.2 19.0 4.0
Syk inhibitor Hs Inhibitor Inhibition 21.6 8.0 10.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
TBK1 belongs to the IKK-kinase family of enzymes. It is a ubiquitously expressed serine/threonine protein kinase, and constitutes a key regulatory node for several signaling pathways involved in the innate immune response that lead to induction of type I interferons. Several classes of innate sensors including the TLRs and retinoic acid-inducible gene 1 (RIG-I)-like helicases engage TBK1-IRF3 signaling pathways to regulate transcription of type I IFNs. In neuroinflammation TBK1 is involved in TLR-dependent [11] and -independent responses [5]. DNA sensing receptors such as DAI, IFI16, DDX41, and cGAS have all been shown to couple dsDNA recognition to TBK1 activation. STING is a critical mediator of DNA-induced TBK1 activation. Dysregulation of TBK1 activity is associated with autoimmune diseases and cancer, conditions which may be amenable to pharmacological inhibition of TBK1 [10]. Inhibition of TBK1 can also be considered in the context of the so-called type I interferonopathies, a set of rare autoimmune pathologies associated with chronic activation of IFN I responses [13].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 4 GO processes
GO:0006954 inflammatory response TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
GO:0045087 innate immune response TAS
click arrow to show/hide IEA associations
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 9 GO processes
GO:0032479 regulation of type I interferon production TAS
GO:0032480 negative regulation of type I interferon production TAS
GO:0032481 positive regulation of type I interferon production TAS
GO:0032606 type I interferon production TAS
GO:0032727 positive regulation of interferon-alpha production IDA
GO:0032728 positive regulation of interferon-beta production IDA
GO:0071345 cellular response to cytokine stimulus TAS
click arrow to show/hide IEA associations
GO:0045359 positive regulation of interferon-beta biosynthetic process IEA
GO:0060340 positive regulation of type I interferon-mediated signaling pathway IEA
Immuno Process:  Cellular signalling
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:0044565 dendritic cell proliferation IEA
Physiological Consequences of Altering Gene Expression
TBK1 ablation in mice is embryonic lethal. They die at stage E14.5 due to liver degeneration and apoptosis.
Species:  Mouse
Tissue: 
Technique: 
References:  2
Clinically-Relevant Mutations and Pathophysiology
Disease:  Herpetic encephalitis
Synonyms: Herpes simplex encephalitis
Herpes simplex virus encephalitis [Disease Ontology: DOID:0050181]
HSV encephalitis
Disease Ontology: DOID:0050181
Orphanet: ORPHA1930
Clinically-Relevant Mutations and Pathophysiology Comments
Genetic mutations in TBK1 (e.g. increased TBK1 copy number resulting in a gain of function) is a rare cause of primary open angle glaucoma and normal tension glaucoma. Heterozygous loss of function TBK1 mutations are associated with herpes simplex encephalitis in childhood. Both of these associations are to diseases with neuroinflammatory components. TBK1 has now been identified by several studies as an amyotrophic lateral sclerosis (ALS) gene [3,8,23], often in comorbidity with frontotemporal dementia (FTD) [12,18].
General Comments
TBK1 and IKKε 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 [7,20].

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. Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M, Itié A, Wakeham A, Shahinian A, Henzel WJ et al.. (2000) Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription. EMBO J., 19 (18): 4976-85. [PMID:10990461]

3. Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, Couthouis J, Lu YF, Wang Q, Krueger BJ et al.. (2015) Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science, 347 (6229): 1436-41. [PMID:25700176]

4. 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]

5. Cui J, Chen Y, Wang HY, Wang RF. (2014) Mechanisms and pathways of innate immune activation and regulation in health and cancer. Hum Vaccin Immunother, 10 (11): 3270-85. [PMID:25625930]

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. 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]

8. Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Müller K, Marroquin N, Nordin F, Hübers A, Weydt P et al.. (2015) Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci., 18 (5): 631-6. [PMID:25803835]

9. 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]

10. Hasan M, Yan N. (2016) Therapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies. Pharmacol. Res., 111: 336-42. [PMID:27353409]

11. Kawai T, Akira S. (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med, 13 (11): 460-9. [PMID:18029230]

12. Le Ber I, De Septenville A, Millecamps S, Camuzat A, Caroppo P, Couratier P, Blanc F, Lacomblez L, Sellal F, Fleury MC et al.. (2015) TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts. Neurobiology of aging, 30 (11): 3116-e5.

13. Lee-Kirsch MA. (2017) The Type I Interferonopathies. Annu. Rev. Med., 68: 297-315. [PMID:27813875]

14. 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]

15. 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]

16. 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]

17. 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.

18. Pottier C, Bieniek KF, Finch N, van de Vorst M, Baker M, Perkersen R, Brown P, Ravenscroft T, van Blitterswijk M, Nicholson AM et al.. (2015) Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol., 130 (1): 77-92. [PMID:25943890]

19. 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]

20. 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]

21. 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

22. Vu HL, Aplin AE. (2014) Targeting TBK1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma. Mol. Cancer Res., 12 (10): 1509-19. [PMID:24962318]

23. Williams KL, McCann EP, Fifita JA, Zhang K, Duncan EL, Leo PJ, Marshall M, Rowe DB, Nicholson GA, Blair IP. (2015) Novel TBK1 truncating mutation in a familial amyotrophic lateral sclerosis patient of Chinese origin. Neurobiology of aging, 36 (12): 31-36.

24. 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: TANK binding kinase 1. Last modified on 21/03/2019. Accessed on 17/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2237.