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TANK binding kinase 1

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Target id: 2237

Nomenclature: TANK binding kinase 1

Abbreviated Name: TBK1

Family: IKK family

Contents:

Gene and Protein Information Click here for help
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 Click here for help
NAK | TANK-binding kinase 1
Database Links Click here for help
Alphafold Q9UHD2 (Hs), Q9WUN2 (Mm)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL5408 (Hs), CHEMBL2189160 (Mm)
Ensembl Gene ENSG00000183735 (Hs), ENSMUSG00000020115 (Mm), ENSRNOG00000005528 (Rn)
Entrez Gene 29110 (Hs), 56480 (Mm), 299827 (Rn)
Human Protein Atlas ENSG00000183735 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:29110 (Hs), mmu:56480 (Mm), rno:299827 (Rn)
OMIM 604834 (Hs)
Orphanet ORPHA318865 (Hs)
Pharos Q9UHD2 (Hs)
RefSeq Nucleotide NM_013254 (Hs), NM_019786 (Mm), NM_001106786 (Rn)
RefSeq Protein NP_037386 (Hs), NP_062760 (Mm), NP_001100256 (Rn)
SynPHARM 81113 (in complex with MRT67307)
UniProtKB Q9UHD2 (Hs), Q9WUN2 (Mm)
Wikipedia TBK1 (Hs)
Selected 3D Structures Click here for help
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 Click here for help
EC Number: 2.7.11.1

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
TBK1 PROTAC 3i Small molecule or natural product Hs Inhibition 8.9 pKd 6
⤷ pKd 8.9 (Kd 1.3x10-9 M) [6]
Description: BInding affinity for the TBK1 binding moeity of the PROTAC
GSK8612 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition ~8.0 pKd 25
⤷ pKd ~8.0 (Kd ~1x10-8 M) [25]
Description: In a Kinobeads assay using lysates from HEK293/K-562/Placenta/HepG2 cells.
MPI-0485520 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.7 pIC50 21
⤷ pIC50 8.7 (IC50 2x10-9 M) [21]
Description: Using a Kinase Hotspot® assay.
BAY-985 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.7 pIC50 17
⤷ pIC50 8.7 (IC50 2x10-9 M) [17]
Description: Inhibition at low ATP concentration.
AZ13102909 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 26
⤷ pIC50 8.3 (IC50 5x10-9 M) [26]
Description: In vitro biochemical assay.
BX-795 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.2 pIC50 5
⤷ pIC50 8.2 (IC50 6x10-9 M) [5]
compound 17d [PMID: 23099093] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.2 pIC50 19
⤷ pIC50 8.2 (IC50 6x10-9 M) [19]
SR8185 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition >8.0 pIC50 18
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [18]
Description: In an enzyme assay.
compound II [PMID: 21329883] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.9 pIC50 20
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [20]
Description: In a biochemical assay using purified recombinant enzyme.
MRT67307 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.7 pIC50 4
⤷ pIC50 7.7 (IC50 1.9x10-8 M) [4]
compound 6 [PMID: 34333981] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 9
⤷ pIC50 7.2 (IC50 6.6x10-8 M) [9]
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 23
⤷ pIC50 5.7 – 6.0 (IC50 2x10-6 – 1x10-6 M) [23]
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: 8,28
Key to terms and symbols Click column headers to sort
Target used in screen: TBK1
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.1 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.0 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.7 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.6 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.9 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.9 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 6.9 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand 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 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: 1,12
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition -0.5 1.5 0.5
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 3.2 2.0 1.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 4.4 1.0 0.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 5.3 -1.0 3.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 7.4 54.0 62.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 10.3 -1.0 -2.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 16.3 15.0 1.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 18.8 7.0 0.0
STO609 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 20.2 19.0 4.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand 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 [14] and -independent responses [7]. 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 [13]. 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 [16].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Physiological Consequences of Altering Gene Expression Click here for help
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 Click here for help
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 [3,11,27], often in comorbidity with frontotemporal dementia (FTD) [15,22].
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 [10,24].

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. 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]

6. Crew AP, Raina K, Dong H, Qian Y, Wang J, Vigil D, Serebrenik YV, Hamman BD, Morgan A, Ferraro C et al.. (2018) Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1. J Med Chem, 61 (2): 583-598. [PMID:28692295]

7. 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]

8. 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]

9. Drewry DH, Annor-Gyamfi JK, Wells CI, Pickett JE, Dederer V, Preuss F, Mathea S, Axtman AD. (2022) Identification of Pyrimidine-Based Lead Compounds for Understudied Kinases Implicated in Driving Neurodegeneration. J Med Chem, 65 (2): 1313-1328. [PMID:34333981]

10. 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]

11. 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]

12. 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]

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

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

15. 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. Neurobiol Aging, 36 (11): 3116.e5-3116.e8. [PMID:26476236]

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

17. 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]

18. 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]

19. 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]

20. 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]

21. 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.

22. 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]

23. 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]

24. 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]

25. 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]

26. 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]

27. 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. Neurobiol Aging, 36 (12): 3334.e1-3334.e5. [PMID:26350399]

28. 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 03/11/2022. Accessed on 17/09/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2237.