TBK1

Summary

TBK1 (TANK binding kinase 1, HGNC:11584) is a protein-coding gene on chromosome 12q14.2, encoding Serine/threonine-protein kinase TBK1 (Q9UHD2). Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. In precision oncology, TBK1 Overexpression confers sensitivity to AZ909 + Selumetinib in Melanoma (CIViC Level D).

The NF-kappa-B (NFKB) complex of proteins is inhibited by I-kappa-B (IKB) proteins, which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the IKB proteins by IKB kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation and nuclear translocation of the NFKB complex. The protein encoded by this gene is similar to IKB kinases and can mediate NFKB activation in response to certain growth factors. The protein is also an important kinase for antiviral innate immunity response.

Source: NCBI Gene 29110 — RefSeq curated summary.

At a glance

• Gene–disease (curated): frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 619 total — 59 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 151
• Druggable target: yes — 38 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_013254

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11584
Approved symbol	TBK1
Name	TANK binding kinase 1
Location	12q14.2
Locus type	gene with protein product
Status	Approved
Aliases	NAK
Ensembl gene	ENSG00000183735
Ensembl biotype	protein_coding
OMIM	604834
Entrez	29110

Gene structure

Transcript identifiers

Ensembl transcripts: 73 — 29 nonsense_mediated_decay, 23 protein_coding, 14 retained_intron, 7 protein_coding_CDS_not_defined

ENST00000331710, ENST00000536906, ENST00000538890, ENST00000539810, ENST00000540417, ENST00000541805, ENST00000545025, ENST00000545392, ENST00000650708, ENST00000650762, ENST00000650786, ENST00000650790, ENST00000650997, ENST00000651014, ENST00000651262, ENST00000651878, ENST00000651889, ENST00000651947, ENST00000652389, ENST00000652537, ENST00000652657, ENST00000676469, ENST00000676490, ENST00000676521, ENST00000676539, ENST00000676551, ENST00000676587, ENST00000676593, ENST00000676654, ENST00000676684, ENST00000676774, ENST00000676809, ENST00000676901, ENST00000676912, ENST00000676930, ENST00000676983, ENST00000677016, ENST00000677112, ENST00000677242, ENST00000677313, ENST00000677435, ENST00000677499, ENST00000677545, ENST00000677549, ENST00000677632, ENST00000677641, ENST00000677670, ENST00000677686, ENST00000677714, ENST00000677759, ENST00000677831, ENST00000677858, ENST00000677973, ENST00000678079, ENST00000678125, ENST00000678180, ENST00000678197, ENST00000678235, ENST00000678368, ENST00000678430, ENST00000678567, ENST00000678582, ENST00000678718, ENST00000678738, ENST00000678808, ENST00000678992, ENST00000678996, ENST00000679010, ENST00000679050, ENST00000679065, ENST00000679302, ENST00000911930, ENST00000970119

RefSeq mRNA: 1 — MANE Select: NM_013254 NM_013254

CCDS: CCDS8968

Canonical transcript exons

ENST00000331710 — 21 exons

Exon	Start	End
ENSE00001292692	64480012	64480122
ENSE00001294086	64484303	64484499
ENSE00001294105	64496949	64497050
ENSE00001300846	64495699	64495775
ENSE00001301106	64466901	64467082
ENSE00001303825	64495483	64495604
ENSE00001303859	64488487	64488588
ENSE00001304844	64501330	64502114
ENSE00001306014	64497648	64497754
ENSE00001308476	64481842	64482021
ENSE00001309870	64485455	64485513
ENSE00001315222	64496367	64496406
ENSE00001317749	64474230	64474390
ENSE00001318600	64464334	64464463
ENSE00001322789	64485926	64486017
ENSE00001323888	64497968	64498039
ENSE00001324110	64490041	64490119
ENSE00001328105	64455840	64455957
ENSE00003598345	64460189	64460329
ENSE00003682738	64497163	64497259
ENSE00003850813	64452120	64452187

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 96.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.9607 / max 488.4779, expressed in 1798 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126447	24.4163	1792
126448	1.0147	253
126445	0.2750	126
126446	0.2547	100

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	96.84	gold quality
calcaneal tendon	UBERON:0003701	96.02	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.65	gold quality
secondary oocyte	CL:0000655	95.46	gold quality
adrenal tissue	UBERON:0018303	94.50	gold quality
sperm	CL:0000019	94.40	gold quality
monocyte	CL:0000576	94.00	gold quality
mononuclear cell	CL:0000842	93.91	gold quality
leukocyte	CL:0000738	93.80	gold quality
sural nerve	UBERON:0015488	93.39	gold quality
ventricular zone	UBERON:0003053	93.23	gold quality
male germ cell	CL:0000015	93.21	gold quality
tonsil	UBERON:0002372	93.07	gold quality
bone marrow cell	CL:0002092	92.99	gold quality
tongue squamous epithelium	UBERON:0006919	92.97	silver quality
corpus callosum	UBERON:0002336	92.75	gold quality
gingival epithelium	UBERON:0001949	92.74	gold quality
esophagus squamous epithelium	UBERON:0006920	92.58	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.40	gold quality
cartilage tissue	UBERON:0002418	92.28	gold quality
pericardium	UBERON:0002407	92.24	gold quality
pons	UBERON:0000988	92.23	gold quality
left testis	UBERON:0004533	92.06	gold quality
bone marrow	UBERON:0002371	92.04	gold quality
right testis	UBERON:0004534	91.97	gold quality
subthalamic nucleus	UBERON:0001906	91.95	gold quality
middle temporal gyrus	UBERON:0002771	91.75	gold quality
testis	UBERON:0000473	91.65	gold quality
cardia of stomach	UBERON:0001162	91.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.61	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8894	yes	1548.54
E-MTAB-8142	yes	93.87
E-CURD-88	yes	41.83
E-ANND-3	yes	5.19
E-MTAB-6524	no	93.49
E-HCAD-10	no	7.12

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, DLX4, IRF3, NFKB, SP1

miRNA regulators (miRDB)

59 targeting TBK1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-5580-3P	99.70	69.41	2052

Literature-anchored findings (GeneRIF, showing 40)

• IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2. (PMID:11839743)
• Association of the adaptor TANK with the I kappa B kinase (IKK) regulator connects IKK complexes with IKK epsilon and TBK1 kinases (PMID:12133833)
• IKKepsilon and TBK1 have a pivotal role in coordinating the activation of IRF3 and NF-kappaB in the innate immune response. (PMID:12692549)
• data suggest that intracellular RNP formation contributes to the early recognition of vesicular stomatitis virus infection, activates the catalytic activity of TBK1, and induces transcriptional upregulation of IKKepsilon in epithelial cells (PMID:15367631)
• NAK is a component of the TNFalpha.TNFR1 signaling complex and has a physiological role in the TNFalpha-mediated response (PMID:15485837)
• IL-1-inducible phosphorylation of p65 NFkB is mediated by multiple protein kinases including IKKalpha, IKKbeta, IKKepsilon, TBK1, and an unknown kinase and couples p65 to TAFII31-mediated IL-8 transcription (PMID:15489227)
• TBK1 has a role in human cytomegalovirus-infected vascular smooth muscle cells (PMID:15619605)
• HCV NS3 protein interacts directly with TBK1, and that this binding results in the inhibition of the association between TBK1 and IRF-3, which leads to the inhibition of IRF-3 activation (PMID:15841462)
• studies define one important mechanism of NF-kappaB-inducing kinase (NIK) regulation and the central role of NIK stabilization in the induction of NF-kappaB2 precursor protein p100 processing (PMID:16223731)
• interferon-A promoter organization differentially affects virus-induced expression and responsiveness to TBK1 and IKKepsilon (PMID:16380379)
• The present study identified a specific interaction between IRF3 and chaperone heat-shock protein of 90 kDa (Hsp90).In addition, TBK1 is found to be a client protein of Hsp90 in vivo. (PMID:16394098)
• TBK1 is important for vascularization and subsequent tumor growth (PMID:16537515)
• TBK1 and IKK epsilon directly phosphorylate the C-terminal domain of cRel in vitro and in vivo and regulate nuclear accumulation of cRel. (PMID:16888014)
• Interferon Regulatory Factor-3 is a direct target of TBK-1 phosphorylation (PMID:16973572)
• These observations define the mechanistic contribution of RalGTPases to cancer cell survival and reveal the RalB/Sec5 effector complex as a component of TBK1-dependent innate immune signaling. (PMID:17018283)
• TANK may be a critical adaptor that regulates the assembly of the TANK-binding kinase 1-inducible IkappaB kinase complex with upstream signaling molecules in multiple antiviral pathways (PMID:17327220)
• analysis of a two-step phosphorylation model for IRF-3 activation mediated by TBK1 (PMID:17526488)
• results suggest that efficient signal transduction upon viral infection requires SINTBAD, TANK and NAP1 because they link TBK1 and IKKi to virus-activated signalling cascades (PMID:17568778)
• Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF. (PMID:17823124)
• The OPTN[E50K] mutant associated with Primary Open Angle Glaucoma (POAG) displayed strikingly enhanced binding to TBK1, suggesting that this interaction may contribute to familial POAG caused by this mutation. (PMID:18307994)
• distinct scaffold proteins assemble IKK, and potentially TBK1 and IKK-epsilon subcomplexes, in a stimulus-specific manner, which might be a mechanism to achieve specificity [review] (PMID:18353649)
• The TBK-1 pathway may be an important cross-link between angiogenesis and inflammation representing a possible target for anti-tumor therapy. (PMID:18508731)
• DDX3X is a critical effector of TBK1 that is necessary for type I IFN induction. (PMID:18583960)
• These findings indicate that the Hantavirus NY-1V Gn cytoplasmic tail forms a complex with TRAF3 which disrupts the formation of TBK1-TRAF3 complexes and downstream signaling responses required for IFN-beta transcription. (PMID:18614628)
• Upon Sendai virus (SeV) infection, TBK1s is induced in both human and mouse cells and binds to RIG-1, disrupting the interaction between RIG-I and VISA (PMID:18977754)
• a novel TLR-independent pathogen-sensing mechanism in immune and nonimmune cells that converges on TBK1 and IFN regulatory factor 3 for activation of IFN-beta gene expression. (PMID:19017982)
• These data suggest that VP35 exerts its interferon-antagonist function, at least in part, by blocking necessary interactions between the kinases IKKepsilon and TBK-1 and their normal interaction partners, including their substrates, IRF-3 and IRF-7. (PMID:19153231)
• the phosphorylation of Ser-172 and the activation of TBK1 and IKKepsilon are catalyzed by a distinct protein kinase(s) in vivo (PMID:19307177)
• Major outer protein of Treponema lecithinolyticum (Msp) induces interferon-beta expression and subsequent up-regulation of IP-10 and RANTES via TBK1 and interferon regulatory factor-3 signaling secondary to lipid raft activation. (PMID:19380831)
• Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression (PMID:19847166)
• Activation of IRF3 and IRF3-dependent gene expressions was dependent on TAK1 and TANK-binding kinase 1 (TBK1). (PMID:19955181)
• Data suggest that TBK1 may play a role in the hepatitis B viral X protein -mediated activation of the NF-kappaB signaling pathway and the development of hepatocellular carcinoma . (PMID:19958770)
• results demonstrate TBK1-IKKi to be novel substrates for A20 and further identify a novel mechanism whereby A20 and TAX1BP1 restrict antiviral signaling by disrupting a TRAF3-TBK1-IKKi signaling complex (PMID:20304918)
• TBK1 directly interacts with VPS37C, a subunit of endosomal sorting complex required for transport-I (ESCRT-I) in the multivesicular body (MVB) pathway, without affecting the ultrastructure or general function of MVB. (PMID:21270402)
• NF-kB p65 binds to 27 of the mutant p53-bound promoters, indicating that mutant p53 could influence the transcriptional output of these NF-kB target genes. (PMID:21332394)
• PLP2(papain-like protease domain 2 (PLP2), a catalytic domain of the nonstructural protein 3 (nsp3) of MHV-A59) may also target TANK-binding kinase-1 (TBK1), the upstream kinase of IRF3 in the IFN signaling pathway. (PMID:21364999)
• Extra copies of the encompassed TBK1 gene is likely responsible for cases of normal tension glaucoma. (PMID:21447600)
• IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. (PMID:21464307)
• inhibition of signaling reduces growth of medulloblastoma (PMID:21492457)
• Mechanistically, the tetratrico-peptide repeat motif (E164/E165) of IFIT3 interacts with the N terminus (K38) of TBK1, thus bridging TBK1 to MAVS on the mitochondrion (PMID:21813773)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbk1	ENSDARG00000103095
mus_musculus	Tbk1	ENSMUSG00000020115
rattus_norvegicus	Tbk1	ENSRNOG00000005528
drosophila_melanogaster	IKKepsilon	FBGN0086657

Paralogs (3): IKBKB (ENSG00000104365), CHUK (ENSG00000213341), IKBKE (ENSG00000263528)

Protein

Protein identifiers

Serine/threonine-protein kinase TBK1 — Q9UHD2 (reviewed: Q9UHD2)

Alternative names: NF-kappa-B-activating kinase, T2K, TANK-binding kinase 1

All UniProt accessions (46): A0A494BZY3, A0A494C045, A0A494C079, A0A494C0A8, A0A494C0R4, A0A494C0X2, A0A494C148, A0A494C167, A0A494C1I2, A0A494C1M6, A0A7I2V2F4, A0A7I2V2N0, Q9UHD2, A0A7I2V2N9, A0A7I2V2V9, A0A7I2V322, A0A7I2V387, A0A7I2V3B7, A0A7I2V3E0, A0A7I2V3P0, A0A7I2V3S9, A0A7I2V3Y6, A0A7I2V463, A0A7I2V476, A0A7I2V4C0, A0A7I2V4M2, A0A7I2V4M8, A0A7I2V4S0, A0A7I2V4W4, A0A7I2V4Y1, A0A7I2V4Z2, A0A7I2V502, A0A7I2V573, A0A7I2V5W0, A0A7I2V5Y4, A0A7I2V5Z0, A0A7I2V615, A0A7I2V636, A0A7I2V643, A0A7I2V646, A0A7I2YQG1, A0A7I2YQG4, A0A7I2YQM3, F5GZI4, F5H1A3, F5H206

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Plays a key role in IRF3 activation: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1. Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce expression of interferons. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on ‘Ser-177’, thus enhancing LC3 binding affinity and antibacterial autophagy. Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex, promoting autophagosome maturation. Phosphorylates ATG8 proteins MAP1LC3C and GABARAPL2, thereby preventing their delipidation and premature removal from nascent autophagosomes. Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, which leads to a negative impact on insulin sensitivity. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates Borna disease virus (BDV) P protein. Plays an essential role in the TLR3- and IFN-dependent control of herpes virus HSV-1 and HSV-2 infections in the central nervous system. Acts both as a positive and negative regulator of the mTORC1 complex, depending on the context: activates mTORC1 in response to growth factors by catalyzing phosphorylation of MTOR, while it limits the mTORC1 complex by promoting phosphorylation of RPTOR. Acts as a positive regulator of the mTORC2 complex by mediating phosphorylation of MTOR, leading to increased phosphorylation and activation of AKT1. Phosphorylates and activates AKT1. Involved in the regulation of TNF-induced RIPK1-mediated cell death, probably acting via CYLD phosphorylation that in turn controls RIPK1 ubiquitination status. Also participates in the differentiation of T follicular regulatory cells together with the receptor ICOS.

Subunit / interactions. Homodimer. Interacts with DDX3X, TIRAP and TRAF2. Part of a ternary complex consisting of TANK, TRAF2 and TBK1. Interacts with AZI2, TANK and TBKBP1; these interactions are mutually exclusive and mediate TBK1 activation. Interacts with GSK3B; this interaction promotes TBK1 self-association and autophosphorylation. Interacts with SIKE1; SIKE1 is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation. Interacts with IRF3, leading to IRF3 phosphorylation. Interacts with RIGI. Interacts with CYLD. Interacts with OPTN and TRAF3. Interacts with SRC. Interacts with the exocyst complex subunit SEC5/EXOC2; this interaction is sufficient to trigger TBK1 activity. Interacts with STING1, leading to STING1 phosphorylation. Interacts with IFIT3 (via N-terminus). Interacts with MAVS; interaction only takes place in the presence of IFIT3 and leads to MAVS phosphorylation. Interacts (via protein kinase domain) with TTLL12 (via TTL domain); the interaction prevents MAVS binding to TBK1. Interacts with TICAM1; this interaction is enhanced in the presence of WDFY1 and leads to TICAM1 phosphorylation. Interacts with TRIM26. Interacts with TRIM23. Interacts with TTC4 and IKBKE. Interacts with HNRNPA2B1. Interacts with DDX3X. Interacts with TRIM14. Interacts with CEP170; efficient complex formation may be dependent on the presence of CCDC61. Interacts with TRAF3IP3. Interacts with HSP90AA1; the interaction mediates TBK1 association with TOMM70. Interacts with TAX1BP1. Interacts with kinase IKBKB; the complex interacts with STAT1, leading to phosphorylation of STAT1 on ‘Thr-749’ by IKBKB. Interacts with ICOS; this interaction is critical for the maturation of T follicular regulatory cells. Interacts with RNF144B; this interaction prevents TBK1 phosphorylation and subsequent activation. Interacts with ASB8; this interaction promotes TBK1 proteasomal degradation. Forms a ternary complex with ZNF268 and SETD4; the interaction with SETD4 is ZNF268-dependent and leads to TBK1 monomethylation, which enhances its interaction with IRF3 and MAVS. (Microbial infection) Interacts with Borna disease virus (BDV) P protein leading to its phosphorylation. (Microbial infection) Interacts with Ebola virus protein VP35. (Microbial infection) Interacts with HCV NS3; this interaction leads to inhibition of cellular antiviral response by blocking necessary interactions between the TBK1 and its substrates IRF3 and IRF7. (Microbial infection) Interacts with human herpesvirus 1 protein ICP34.5. (Microbial infection) Interacts with Zika virus non-structural protein 1/NS1 and non-structural protein 4B/NS4B. (Microbial infection) Interacts with SARS-CoV-2 non-structural protein 6; this interaction decreases IRF3 phosphorylation by 57%, which leads to reduced IFN-beta (IFNB) production. Interacts with SARS-CoV-2 helicase; this interaction inhibits TBK1 phosphorylation and decreases IRF3 phosphorylation by 75%, which leads to reduced IFN-beta production. Interacts with SARS-CoV-2 M protein; the interaction promotes TBK1 degradation via ‘Lys-48’-linked ubiquitination. (Microbial infection) Interacts with human cytomegalovirus protein UL35; this interaction inhibits type I interferon production. (Microbial infection) Interacts with heartland virus NSs; this interaction antagonizes TBK1 phosphorylation and inhibits TBK1-IRF3 interaction and thus the establishment of an antiviral state. (Microbial infection) Interacts (via N-terminus) with Severe fever with thrombocytopenia virus (SFTSV) NSs; this interaction antagonizes TBK1 phosphorylation and sequesters TBK1 in NSs-induced cytoplasmic inclusion bodies thereby inhibiting the IFN responses.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitous with higher expression in testis. Expressed in the ganglion cells, nerve fiber layer and microvasculature of the retina.

Post-translational modifications. Autophosphorylation at Ser-172 activates the kinase, and is an essential step for virus-triggered signaling. Phosphorylated by IKBKB/IKKB at Ser-172. Phosphorylation requires homodimerization and ubiquitination at Lys-30 and Lys-401. Dephosphorylated at Ser-172 by PPM1B and this negatively regulates its role in mediating antiviral response. ‘Lys-63’-linked polyubiquitination by MIB1 after RNA virus infection, or by NRDP1 after LPS stimulation at Lys-30 and Lys-401, participates in kinase activation. ‘Lys-48’-linked polyubiquitination at Lys-670 by DTX4 leads to proteasomal degradation. ‘Lys-48’-linked polyubiquitination by TRAIP also leads to proteasomal degradation. ‘Lys-48’-linked polyubiquitination by TRAF7; leading to proteasomal degradation. ‘Lys-63’-linked polyubiquitination by RNF128 at Lys-30 and Lys-401 leads to the activation of antiviral responses. ‘Lys-48’-linked polyubiquitination after ’lys-33’-linked deubiquitination by USP38 promotes TBK1 degradation. (Microbial infection) Interaction with SARS-CoV-2 M protein induces ‘Lys-48’-linked ubiquitination which leads to proteasomal degradation. (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1 on both ‘Lys-48’ and ‘Lys-63’-linked ubiquitin chains; leading to inhibition of type I interfewron production. Monomethylation at Lys-607 by SETD4 maximizes TBK1 activation and promotes efficient interferon signaling.

Disease relevance. Glaucoma 1, open angle, P (GLC1P) [MIM:177700] A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. GLC1P is characterized by early onset, thin central corneas and low intraocular pressure. The disease may be caused by variants affecting the gene represented in this entry. A copy number variation on chromosome 12q14 consisting of a 300 kb duplication that includes TBK1, XPOT, RASSF3 and GNS has been found in individuals affected by glaucoma. TBK1 is the most likely candidate for the disorder. Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (FTDALS4) [MIM:616439] A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. The disease is caused by variants affecting the gene represented in this entry. Encephalopathy, acute, infection-induced, 8, herpes-specific (IIAE8) [MIM:617900] A rare, often fatal complication of herpes simplex infection, caused by virus spreading in the central nervous system. Disease manifestations include low-grade fever, severe headache, nausea, vomiting, and lethargy. Neurological features include confusion, acute memory disturbances, disorientation, behavioral changes, hemiparesis and seizures. Disease susceptibility is associated with variants affecting the gene represented in this entry. Autoinflammation with arthritis and vasculitis (AIARV) [MIM:620880] An autosomal recessive disorder characterized by onset of chronic and systemic autoinflammation in infancy or early childhood. Affected individuals have recurrent fever, erythematous skin rashes, vasculitis, oral aphthous lesions, and polyarthritis. Additional variable features are poor overall growth, microcytic anemia, mild intellectual disability, and seizures. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Comprises A N-terminal kinase domain, a ubiquitin-like domain and a C-terminal coiled-coil region mediating homodimerization.

Miscellaneous. In cancer cells, pathological TBK1 activation promotes oncogenic transformation by suppressing programmed cell death. Mechanistically, the RALB-SEC5/EXOC2-TBK1 signaling cascade seems to participate in both innate immune signaling and cell transformation. Additionally, TBK1 supports oncogenesis by directly phosphorylating and activating AKT1 at the exocyst.

Similarity. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.

RefSeq proteins (1): NP_037386* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR041087	TBK1_ULD	Domain
IPR041309	TBK1_CC1	Domain
IPR051180	IKK	Family

Pfam: PF00069, PF18394, PF18396

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (139 total): sequence variant 37, mutagenesis site 31, helix 25, strand 24, turn 7, modified residue 3, cross-link 3, domain 2, coiled-coil region 2, binding site 2, chain 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
5EP6	X-RAY DIFFRACTION	1.45
4EFO	X-RAY DIFFRACTION	1.77
4EUU	X-RAY DIFFRACTION	1.8
5EOF	X-RAY DIFFRACTION	2.05
4IM0	X-RAY DIFFRACTION	2.4
4IM2	X-RAY DIFFRACTION	2.5
5EOA	X-RAY DIFFRACTION	2.5
4EUT	X-RAY DIFFRACTION	2.6
4IWO	X-RAY DIFFRACTION	2.61
6RSU	X-RAY DIFFRACTION	2.75
4IWQ	X-RAY DIFFRACTION	3
4IWP	X-RAY DIFFRACTION	3.06
6RSR	X-RAY DIFFRACTION	3.15
6CQ0	X-RAY DIFFRACTION	3.19
6BOD	X-RAY DIFFRACTION	3.2
6CQ4	X-RAY DIFFRACTION	3.2
6RST	X-RAY DIFFRACTION	3.29
6NT9	ELECTRON MICROSCOPY	3.3
6BNY	X-RAY DIFFRACTION	3.34
4IM3	X-RAY DIFFRACTION	3.34
6CQ5	X-RAY DIFFRACTION	3.35
6O8B	X-RAY DIFFRACTION	3.4
6BOE	X-RAY DIFFRACTION	3.6
5W5V	X-RAY DIFFRACTION	3.65
4IW0	X-RAY DIFFRACTION	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHD2-F1	89.90	0.72

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 135 (proton acceptor)

Ligand- & substrate-binding residues (2): 15–23; 38

Post-translational modifications (6): 607, 716, 30, 401, 670, 172

Mutagenesis-validated functional residues (31):

Position	Phenotype
30	decreases ubiquitination. abolishes ubiquitination, phosphorylation and kinase activity; when associated with r-401.
33	decreases phosphorylation and kinase activity.
38	loss of kinase activity.
135	loss of kinase activity.
172	loss of kinase activity. no effect on dimerization. loss of usp38-mediated degradation.
172	decreased kinase activity.
316	decreases kinase activity. no effect on phosphorylation.
325	abolishes phosphorylation and kinase activity.
355	decreases phosphorylation and kinase activity. abolishes dimerization; when associated with a-357 or r-448.
357	decreases phosphorylation and kinase activity. abolishes dimerization; when associated with r-355.
401	decreases ubiquitination. abolishes ubiquitination, phosphorylation and kinase activity; when associated with r-30.
448	decreases phosphorylation and kinase activity. abolishes dimerization; when associated with r-355.
459	abolishes dimerization and decreases kinase activity but no effect on phosphorylation; when associated with e-466 and e-
466	abolishes dimerization and decreases kinase activity but no effect on phosphorylation; when associated with e-459 and e-
470	abolishes dimerization and decreases kinase activity but no effect on phosphorylation; when associated with e-459 and e-
547	decreases phosphorylation and kinase activity. abolishes dimerization.
577	decreases kinase activity. reduced phosphorylation of sting1.
578	reduced phosphorylation of sting1.
580	decreases kinase activity.
581	reduced phosphorylation of sting1.
582	decreases kinase activity.
584	decreased ifnb1 promoter activation.
589	decreases phosphorylation and kinase activity.
607	attenuated homodimerization during sendai virus infection; decreased interaction with irf3 or mavs; decreased ifnb1 prom
670	abrogates both ’lys-48’-linked and ’lys-33’-linked ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

47 pathways

ID	Pathway
R-HSA-1606341	IRF3 mediated activation of type 1 IFN
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-3134975	Regulation of innate immune responses to cytosolic DNA
R-HSA-3249367	STAT6-mediated induction of chemokines
R-HSA-3270619	IRF3-mediated induction of type I IFN
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-9008059	Interleukin-37 signaling
R-HSA-9013973	TICAM1-dependent activation of IRF3/IRF7
R-HSA-918233	TRAF3-dependent IRF activation pathway
R-HSA-933541	TRAF6 mediated IRF7 activation
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-936964	Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-9824878	Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7
R-HSA-9828211	Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1606322	ZBP1(DAI) mediated induction of type I IFNs
R-HSA-162582	Signal Transduction
R-HSA-1632852	Macroautophagy
R-HSA-1643685	Disease
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades

MSigDB gene sets: 622 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GSE45365_NK_CELL_VS_BCELL_UP, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_PEPTIDYL_SERINE_MODIFICATION, AAGCCAT_MIR135A_MIR135B, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GOBP_RESPONSE_TO_TYPE_I_INTERFERON

GO Biological Process (50): activation of innate immune response (GO:0002218), cytoplasmic pattern recognition receptor signaling pathway (GO:0002753), protein phosphorylation (GO:0006468), inflammatory response (GO:0006954), canonical NF-kappaB signal transduction (GO:0007249), response to virus (GO:0009615), positive regulation of autophagy (GO:0010508), negative regulation of gene expression (GO:0010629), macroautophagy (GO:0016236), positive regulation of macroautophagy (GO:0016239), peptidyl-serine phosphorylation (GO:0018105), peptidyl-threonine phosphorylation (GO:0018107), regulation of type I interferon production (GO:0032479), positive regulation of type I interferon production (GO:0032481), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), toll-like receptor 4 signaling pathway (GO:0034142), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), dendritic cell proliferation (GO:0044565), innate immune response (GO:0045087), positive regulation of transcription by RNA polymerase II (GO:0045944), defense response to Gram-positive bacterium (GO:0050830), defense response to virus (GO:0051607), type I interferon-mediated signaling pathway (GO:0060337), positive regulation of type I interferon-mediated signaling pathway (GO:0060340), T follicular helper cell differentiation (GO:0061470), antiviral innate immune response (GO:0140374), cGAS/STING signaling pathway (GO:0140896), negative regulation of TORC1 signaling (GO:1904262), positive regulation of TORC1 signaling (GO:1904263), positive regulation of xenophagy (GO:1904417), positive regulation of TORC2 signaling (GO:1904515), cytoplasmic translation (GO:0002181), immune system process (GO:0002376), protein import into nucleus (GO:0006606), response to stress (GO:0006950), mRNA transcription (GO:0009299), regulation of gene expression (GO:0010468), signal transduction involved in regulation of gene expression (GO:0023019), cellular response to nutrient levels (GO:0031669)

GO Molecular Function (13): nucleic acid binding (GO:0003676), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein phosphatase binding (GO:0019903), identical protein binding (GO:0042802), phosphoprotein binding (GO:0051219), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), serine/threonine protein kinase complex (GO:1902554)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
DDX58/IFIH1-mediated induction of interferon-alpha/beta	3
STING mediated induction of host immune responses	2
TNF signaling	2
ZBP1(DAI) mediated induction of type I IFNs	1
Innate Immune System	1
Cytosolic sensors of pathogen-associated DNA	1
Mitophagy	1
Interleukin-1 family signaling	1
Toll Like Receptor 3 (TLR3) Cascade	1
TRIF (TICAM1)-mediated TLR4 signaling	1
SARS-CoV Infections	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1
TICAM1-dependent activation of IRF3/IRF7	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of cytokine production	2
autophagy	2
protein phosphorylation	2
type I interferon production	2
positive regulation of type I interferon production	2
binding	2
protein kinase activity	2
protein binding	2
activation of immune response	1
positive regulation of innate immune response	1
pattern recognition receptor signaling pathway	1
intracellular receptor signaling pathway	1
phosphorylation	1
protein modification process	1
defense response	1
intracellular signaling cassette	1
response to other organism	1
positive regulation of catabolic process	1
regulation of autophagy	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
autophagosome assembly	1
positive regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
peptidyl-serine modification	1
peptidyl-threonine modification	1
regulation of cytokine production	1
regulation of type I interferon production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
cell surface toll-like receptor signaling pathway	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
mononuclear cell proliferation	1

Protein interactions and networks

STRING

4204 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBK1	IRF3	Q14653	999
TBK1	MAVS	Q7Z434	999
TBK1	TANK	Q92844	998
TBK1	TRAF3	Q13114	998
TBK1	TBKBP1	A7MCY6	994
TBK1	OPTN	Q96CV9	994
TBK1	DDX3X	O00571	991
TBK1	RIGI	O95786	984
TBK1	IKBKE	Q14164	983
TBK1	STING1	Q86WV6	980
TBK1	IFNB1	P01574	970
TBK1	TLR3	O15455	969
TBK1	IFIH1	Q9BYX4	960
TBK1	TRAF6	Q9Y4K3	957
TBK1	AZI2	Q9H6S1	955

IntAct

392 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
MAP1LC3B	SQSTM1	psi-mi:“MI:0915”(physical association)	0.980
GABARAPL2	SQSTM1	psi-mi:“MI:0915”(physical association)	0.970
MAP1LC3A	SQSTM1	psi-mi:“MI:0915”(physical association)	0.950
OPTN	TBK1	psi-mi:“MI:0915”(physical association)	0.930
TANK	TBK1	psi-mi:“MI:0915”(physical association)	0.930
TBK1	IRF3	psi-mi:“MI:0915”(physical association)	0.920
STING1	TBK1	psi-mi:“MI:0915”(physical association)	0.900
TBK1	STING1	psi-mi:“MI:0915”(physical association)	0.900
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
TRAF2	TBK1	psi-mi:“MI:0915”(physical association)	0.890
TBK1	TBKBP1	psi-mi:“MI:0914”(association)	0.860
C9orf72	SMCR8	psi-mi:“MI:0217”(phosphorylation reaction)	0.850
rep	TBK1	psi-mi:“MI:0915”(physical association)	0.820
TBK1	rep	psi-mi:“MI:0915”(physical association)	0.820
RB1CC1	ATG13	psi-mi:“MI:0914”(association)	0.820
RARA	NCOR1	psi-mi:“MI:0914”(association)	0.800
STING1	MAVS	psi-mi:“MI:0914”(association)	0.780
TRAF2	HTRA2	psi-mi:“MI:0914”(association)	0.750
TBK1	STX11	psi-mi:“MI:0915”(physical association)	0.740

BioGRID (880): TBK1 (Affinity Capture-Western), TBK1 (Affinity Capture-MS), TBK1 (Reconstituted Complex), TBK1 (Affinity Capture-Western), AKT1 (Affinity Capture-Western), AKT1 (Biochemical Activity), TRAF3 (Affinity Capture-Western), TBK1 (Affinity Capture-Western), TBK1 (Reconstituted Complex), SOCS3 (Reconstituted Complex), SOCS3 (Affinity Capture-Western), IKBKE (Affinity Capture-Western), IKBKE (Reconstituted Complex), SQSTM1 (Biochemical Activity), TBK1 (Affinity Capture-MS)

ESM2 similar proteins: A2AHJ4, A2AQW0, A7MBL8, A9JRL3, F1ND48, O00418, O08796, O08874, O35099, P15056, P28028, P32866, P34908, P53350, P53351, P62205, P70032, P70531, Q07832, Q16513, Q21029, Q2TA25, Q3TWN3, Q4U2V3, Q5E9N5, Q5R4L1, Q5R9R1, Q5ZKK7, Q62673, Q641K1, Q6DD21, Q6RI45, Q6ZN16, Q80V94, Q8AYK6, Q8BPM2, Q8IVH8, Q8QGV2, Q921C3, Q99683

Diamond homologs: A1A5Q6, A2QHV0, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A8WYE4, A8X6H4, C0HKC8, C0HKC9, F4IRW0, F4JBP3, F4JY37, O08678, O08679, O24527, O43293, O54748, O54784, O88764, O94806, P11801, P18652, P22216, P27448, P41892, P42818, P43294, P50527, P53355, Q03141, Q05512, Q0CL79, Q0V7M1, Q13043, Q13188, Q14164

SIGNOR signaling

91 interactions.

A	Effect	B	Mechanism
TICAM1	“up-regulates activity”	TBK1	binding
TBK1	“up-regulates activity”	IRF3	phosphorylation
TBK1	up-regulates	IKBKB	binding
TBK1	up-regulates	RELA	phosphorylation
TBK1	up-regulates	REL	phosphorylation
TBK1	up-regulates	AKT	phosphorylation
TBK1	up-regulates	STAT6	phosphorylation
TBK1	“up-regulates activity”	IKBKE	binding
N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide	down-regulates	TBK1	“chemical inhibition”
TBK1	up-regulates	SQSTM1	phosphorylation
TBK1	up-regulates	IRF5	phosphorylation
TBK1	up-regulates	REL/RELA	phosphorylation
TBK1	“down-regulates quantity by destabilization”	NFKBIA	phosphorylation
TBK1	up-regulates	AKT1	phosphorylation
MAVS	“up-regulates activity”	TBK1	binding
STING1	“up-regulates activity”	TBK1	binding
IKBKE	“up-regulates activity”	TBK1	binding
TRAF3	“up-regulates activity”	TBK1	binding
TBK1	“up-regulates activity”	NfKb-p65/p50	phosphorylation
ORF4b	“down-regulates activity”	TBK1	binding
OPTN	“up-regulates activity”	TBK1	binding
“Non-structural protein 6”	“down-regulates activity”	TBK1	binding
Helicase	“down-regulates activity”	TBK1	binding
TBK1	“up-regulates activity”	STING1	phosphorylation
TRIM23	“up-regulates activity”	TBK1	binding
TBK1	“up-regulates activity”	HTT	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 157 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of tubulin folding intermediates by CCT/TriC	11	41.9×	4e-13
Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	6	41.1×	1e-07
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	11	40.4×	4e-13
Prefoldin mediated transfer of substrate to CCT/TriC	11	39.0×	4e-13
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	7	37.9×	2e-08
MAP3K8 (TPL2)-dependent MAPK1/3 activation	5	32.1×	1e-05
Chaperonin-mediated protein folding	11	29.8×	8e-12
Regulation of NF-kappa B signaling	5	28.6×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of telomere maintenance via telomerase	9	47.4×	2e-11
centriole replication	7	36.9×	7e-08
positive regulation of type I interferon production	11	33.3×	6e-12
cytoplasmic pattern recognition receptor signaling pathway	5	31.9×	4e-05
positive regulation of interferon-beta production	8	22.6×	3e-07
binding of sperm to zona pellucida	7	21.2×	4e-06
toll-like receptor 4 signaling pathway	5	18.9×	3e-04
cellular response to interferon-beta	5	18.9×	3e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

619 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	59
Likely pathogenic	21
Uncertain significance	273
Likely benign	162
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073720	NM_013254.4(TBK1):c.1740del (p.Glu580fs)	Pathogenic
1075012	NM_013254.4(TBK1):c.1934C>G (p.Ser645Ter)	Pathogenic
1368046	NM_013254.4(TBK1):c.1382dup (p.Thr462fs)	Pathogenic
1383659	NM_013254.4(TBK1):c.72dup (p.Arg25fs)	Pathogenic
1395761	NM_013254.4(TBK1):c.1846_1849del (p.Ser616fs)	Pathogenic
1403814	NM_013254.4(TBK1):c.1335G>A (p.Trp445Ter)	Pathogenic
1453082	NM_013254.4(TBK1):c.1972_1973del (p.Leu658fs)	Pathogenic
1453239	NM_013254.4(TBK1):c.1070G>A (p.Arg357Gln)	Pathogenic
1455548	NM_013254.4(TBK1):c.1770_1771del (p.Tyr591fs)	Pathogenic
1460399	NC_000012.11:g.(?64875602)(64879817_?)del	Pathogenic
1497076	NM_013254.4(TBK1):c.1189+1G>A	Pathogenic
1523805	NM_013254.4(TBK1):c.1189+1G>T	Pathogenic
1805458	NM_013254.4(TBK1):c.1856G>A (p.Trp619Ter)	Pathogenic
1878670	NM_013254.4(TBK1):c.738_739del (p.Ser247fs)	Pathogenic
2002131	NM_013254.4(TBK1):c.1917del (p.Asp639fs)	Pathogenic
2029525	NM_013254.4(TBK1):c.944C>A (p.Ser315Ter)	Pathogenic
203435	NM_013254.4(TBK1):c.1349_1352del (p.Ile450fs)	Pathogenic
203437	NM_013254.4(TBK1):c.2138+2T>C	Pathogenic
203438	NM_013254.4(TBK1):c.958del (p.Thr320fs)	Pathogenic
203439	NM_013254.4(TBK1):c.1340+1G>A	Pathogenic
203440	NM_013254.4(TBK1):c.2086G>A (p.Glu696Lys)	Pathogenic
2051653	NM_013254.4(TBK1):c.701+2T>G	Pathogenic
2059613	NM_013254.4(TBK1):c.300_309del (p.Ser102fs)	Pathogenic
2101601	NM_013254.4(TBK1):c.1234del (p.Ala412fs)	Pathogenic
2109276	NM_013254.4(TBK1):c.1305T>A (p.Tyr435Ter)	Pathogenic
2137385	NM_013254.4(TBK1):c.4C>T (p.Gln2Ter)	Pathogenic
2137386	NM_013254.4(TBK1):c.1496C>G (p.Ser499Ter)	Pathogenic
2425832	NC_000012.11:g.(?64849651)(64854129_?)del	Pathogenic
2628090	NM_013254.4(TBK1):c.1372_1373del (p.Val458fs)	Pathogenic
2760183	NM_013254.4(TBK1):c.519del (p.Tyr174fs)	Pathogenic

SpliceAI

3455 predictions. Top by Δscore:

Variant	Effect	Δscore
12:64452183:GCTGG:G	donor_gain	1.0000
12:64452185:TGGG:T	donor_loss	1.0000
12:64452186:GG:G	donor_gain	1.0000
12:64452187:GG:G	donor_gain	1.0000
12:64452188:G:GG	donor_gain	1.0000
12:64452188:GT:G	donor_loss	1.0000
12:64452189:T:G	donor_loss	1.0000
12:64455838:A:AG	acceptor_gain	1.0000
12:64455839:G:GA	acceptor_gain	1.0000
12:64460185:A:AG	acceptor_gain	1.0000
12:64460186:A:G	acceptor_gain	1.0000
12:64464457:GAT:G	donor_gain	1.0000
12:64466889:A:AG	acceptor_gain	1.0000
12:64466889:ATATT:A	acceptor_gain	1.0000
12:64466891:A:AG	acceptor_gain	1.0000
12:64466891:ATT:A	acceptor_gain	1.0000
12:64466892:T:G	acceptor_gain	1.0000
12:64466893:T:A	acceptor_gain	1.0000
12:64466895:TTGAA:T	acceptor_loss	1.0000
12:64466896:T:TA	acceptor_gain	1.0000
12:64466897:GAAGT:G	acceptor_loss	1.0000
12:64466899:A:AG	acceptor_gain	1.0000
12:64466899:AGT:A	acceptor_gain	1.0000
12:64466899:AGTG:A	acceptor_gain	1.0000
12:64466900:G:GG	acceptor_gain	1.0000
12:64466900:GT:G	acceptor_gain	1.0000
12:64466900:GTG:G	acceptor_gain	1.0000
12:64466900:GTGG:G	acceptor_gain	1.0000
12:64467078:ATTTG:A	donor_gain	1.0000
12:64467079:TTTG:T	donor_gain	1.0000

AlphaMissense

4827 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:64455916:G:C	G16R	1.000
12:64455917:G:A	G16D	1.000
12:64455922:G:A	G18R	1.000
12:64455922:G:C	G18R	1.000
12:64455923:G:A	G18E	1.000
12:64455923:G:T	G18V	1.000
12:64455929:C:T	T20I	1.000
12:64455931:G:C	A21P	1.000
12:64455932:C:A	A21E	1.000
12:64455932:C:T	A21V	1.000
12:64455938:T:A	V23D	1.000
12:64455947:G:A	G26E	1.000
12:64455957:G:C	K29N	1.000
12:64455957:G:T	K29N	1.000
12:64460208:C:A	A36D	1.000
12:64460213:A:C	K38Q	1.000
12:64460213:A:G	K38E	1.000
12:64460214:A:T	K38I	1.000
12:64460215:A:C	K38N	1.000
12:64460215:A:T	K38N	1.000
12:64460264:G:A	E55K	1.000
12:64460265:A:T	E55V	1.000
12:64460266:A:C	E55D	1.000
12:64460266:A:T	E55D	1.000
12:64460304:T:A	V68D	1.000
12:64464356:T:C	L84P	1.000
12:64464372:T:G	C89W	1.000
12:64464382:A:C	S93R	1.000
12:64464384:T:A	S93R	1.000
12:64464384:T:G	S93R	1.000

dbSNP variants (sampled 300 via entrez): RS1000194865 (12:64469175 A>C,G), RS1000384459 (12:64455306 C>G), RS1000418016 (12:64501592 T>A), RS1000455135 (12:64476682 C>G), RS1000527933 (12:64476894 G>C), RS1000605463 (12:64469271 C>T), RS1000677183 (12:64467837 T>A), RS1000725150 (12:64456713 G>A), RS1000781030 (12:64461990 C>T), RS1000840113 (12:64456805 G>T), RS1000871476 (12:64502606 C>T), RS1000963415 (12:64456314 T>C), RS1001002096 (12:64463228 C>A,T), RS1001083230 (12:64469518 C>G), RS1001193435 (12:64476071 G>A)

Disease associations

OMIM: gene MIM:604834 | disease phenotypes: MIM:616439, MIM:617900, MIM:620880, MIM:177700, MIM:610551, MIM:137760, MIM:603563

GenCC curated gene-disease

Disease	Classification	Inheritance
frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Definitive	Autosomal dominant
frontotemporal dementia with motor neuron disease	Supportive	Autosomal dominant
autoinflammation with arthritis and vasculitis	Limited	Autosomal recessive
encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Definitive	AD

Mondo (13): frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (MONDO:0014641), encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8 (MONDO:0054754), motor neuron disorder (MONDO:0020128), autoinflammation with arthritis and vasculitis (MONDO:0971173), amyotrophic lateral sclerosis (MONDO:0004976), glaucoma 1, open angle, P (MONDO:0008328), spastic hemiplegia (MONDO:0001168), herpes simplex encephalitis, susceptibility to, 1 (MONDO:0024563), OPTN-related open angle glaucoma (MONDO:0100553), progressive non-fluent aphasia (MONDO:0015059), corticobasal syndrome (MONDO:0018696), hereditary spastic paraplegia 8 (MONDO:0011339), frontotemporal dementia with motor neuron disease (MONDO:0017161)

Orphanet (7): Frontotemporal dementia with motor neuron disease (Orphanet:275872), Motor neuron disease (Orphanet:98503), Amyotrophic lateral sclerosis (Orphanet:803), Herpes simplex virus encephalitis (Orphanet:1930), Progressive non-fluent aphasia (Orphanet:100070), Corticobasal syndrome (Orphanet:454887), Autosomal dominant spastic paraplegia type 8 (Orphanet:100989)

HPO phenotypes

151 total (30 of 151 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000100	Nephrotic syndrome
HP:0000217	Xerostomia
HP:0000508	Ptosis
HP:0000509	Conjunctivitis
HP:0000605	Supranuclear gaze palsy
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000734	Disinhibition
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000750	Delayed speech and language development
HP:0000751	Personality changes
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001259	Coma
HP:0001260	Dysarthria
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001269	Hemiparesis
HP:0001270	Motor delay
HP:0001283	Bulbar palsy

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004692_4	Amyotrophic lateral sclerosis	7.000000e-08
GCST004744_41	Lung adenocarcinoma	6.000000e-07
GCST005647_3	Amyotrophic lateral sclerosis	5.000000e-09
GCST90002385_231	High light scatter reticulocyte count	9.000000e-10
GCST90002386_325	High light scatter reticulocyte percentage of red cells	3.000000e-09
GCST90002405_232	Reticulocyte count	2.000000e-10
GCST90002406_339	Reticulocyte fraction of red cells	9.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D016472	Motor Neuron Disease	C10.574.562; C10.668.467
D057178	Primary Progressive Nonfluent Aphasia	C10.228.140.380.132.600; C10.228.140.380.266.600; C10.574.950.300.600; C10.597.606.150.500.800.100.155.600; C18.452.845.800.300.600; C23.888.592.604.150.500.800.100.155.600; F03.615.400.125.600; F03.615.400.380.600
C566288	Frontotemporal Dementia With Motor Neuron Disease (supp.)
C566748	Glaucoma 1, Open Angle, P (supp.)
C580458	Spastic Paraplegia Type 8 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL3038486 (PROTEIN COMPLEX), CHEMBL4296147 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523711 (PROTEIN-PROTEIN INTERACTION), CHEMBL5408 (SINGLE PROTEIN), CHEMBL6195605 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

38 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 302,406 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL1096	AMLEXANOX	4	4,195
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301607	FILGOTINIB	4	2,905
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL274654	ORANTINIB	3	3,596
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1230165	SILMITASERTIB	2	593
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2
CHEMBL1967878	CENISERTIB	2
CHEMBL1976040	ADAVOSERTIB	2
CHEMBL4116008	CERDULATINIB	2
CHEMBL475251	R-406	2
CHEMBL495727	AT-9283	2
CHEMBL564829	MILCICLIB	2
CHEMBL572878	TOZASERTIB	2
CHEMBL574737	UCN-01	2
CHEMBL1084546	PF-00562271	1

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
TBK1 Overexpression	AZ909 + Selumetinib	Melanoma	Sensitivity/Response	CIViC D	EID1138

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — IKK family

Most potent curated ligand interactions (12 total), top 12:

Ligand	Action	Affinity	Parameter
TBK1 PROTAC 3i	Inhibition	8.89	pKd
BAY-985	Inhibition	8.7	pIC50
MPI-0485520	Inhibition	8.7	pIC50
AZ13102909	Inhibition	8.3	pIC50
BX-795	Inhibition	8.22	pIC50
compound 17d [PMID: 23099093]	Inhibition	8.22	pIC50
GSK8612	Inhibition	8.0	pKd
SR8185	Inhibition	8.0	pIC50
compound II [PMID: 21329883]	Inhibition	7.89	pIC50
MRT67307	Inhibition	7.72	pIC50
compound 6 [PMID: 34333981]	Inhibition	7.18	pIC50
amlexanox	Inhibition	6.0	pIC50

Binding affinities (BindingDB)

1555 measured of 2046 human assays (2063 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-[2-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-2-(oxan-4-yloxy)benzonitrile	IC50	0.29 nM	US-10072001: Tank-binding kinase inhibitor compounds
cyclopropyl(4-{(1R or 1S)-1-[2-({6-[6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone	IC50	0.33 nM	US-10894784: Heteroarylbenzimidazole compounds
(2,2-difluorocyclopropyl)-[4-[1-[2-[[6-(6-pyrrolidin-1-ylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]methanone	IC50	0.473 nM	US-10894784: Heteroarylbenzimidazole compounds
2-[(3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl]oxy-5-[6-[3-methoxy-4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]benzonitrile	IC50	0.481 nM	US-10259811: Tank-binding kinase inhibitor compounds
3,3,3-trifluoro-1-(4-{(1R or 1S)-1-[2-({6-[6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)propan-1-one	IC50	0.49 nM	US-10894784: Heteroarylbenzimidazole compounds
cyclopropyl-[4-[1-[2-[[6-[6-[3-(trifluoromethyl)azetidin-1-yl]pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]methanone	IC50	0.558 nM	US-10894784: Heteroarylbenzimidazole compounds
cyclopropyl-[4-[1-[2-[[6-[1-[(2,2-difluorocyclopropyl)methyl]pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]methanone	IC50	0.564 nM	US-10894784: Heteroarylbenzimidazole compounds
[(1S)-2,2-difluorocyclopropyl]-[4-[1-[2-[[6-[6-[3-(trifluoromethyl)azetidin-1-yl]pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]methanone	IC50	0.566 nM	US-10894784: Heteroarylbenzimidazole compounds
cyclopropyl-[4-[1-[2-[[6-[1-[(2,2-difluorocyclopropyl)methyl]pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]methanone	IC50	0.61 nM	US-10894784: Heteroarylbenzimidazole compounds
(4-{(1R or 1S)-1-[2-({6-[6-(azetidin-1-yl)pyrimidin-4-yl]-1H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)(cyclopropyl)methanone	IC50	0.62 nM	US-10894784: Heteroarylbenzimidazole compounds
1-[4-[1-[2-[[6-[1-[(1-chlorocyclopropyl)methyl]pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-3,3,3-trifluoropropan-1-one	IC50	0.64 nM	US-10894784: Heteroarylbenzimidazole compounds
2-[3,3-difluoro-1-(2-hydroxyacetyl)piperidin-4-yl]oxy-5-[6-[3-methoxy-4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]benzonitrile	IC50	0.687 nM	US-10072001: Tank-binding kinase inhibitor compounds
3,3,3-trifluoro-1-[4-[1-[2-[[6-[6-(methoxymethyl)pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]propan-1-one	IC50	0.7 nM	US-10894784: Heteroarylbenzimidazole compounds
2-(oxan-4-yloxy)-5-[2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]benzonitrile	IC50	0.71 nM	US-10072001: Tank-binding kinase inhibitor compounds
1-[4-[1-[2-[[6-[1-[(2,2-difluorocyclopropyl)methyl]pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-3,3,3-trifluoropropan-1-one	IC50	0.72 nM	US-10894784: Heteroarylbenzimidazole compounds
[4-[1-[2-[[4-chloro-5-[1-[(2,2-difluorocyclopropyl)methyl]pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-cyclopropylmethanone	IC50	0.73 nM	US-10894784: Heteroarylbenzimidazole compounds
1-(4-{(1R or 1S)-1-[2-({6-[6-(azetidin-1-yl)pyrimidin-4-yl]-1H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)-3,3,3-trifluoropropan-1-one	IC50	0.76 nM	US-10894784: Heteroarylbenzimidazole compounds
cyclopropyl(4-{(1R or 1S)-1-[2-({6-[6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl]-1H-benzimidazol-2-yl}amino)pyridin-4-yl]ethyl}piperazin-1-yl)methanone	IC50	0.76 nM	US-10894784: Heteroarylbenzimidazole compounds
5-[2-[4-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-2-(oxan-4-yloxy)benzonitrile	IC50	0.77 nM	US-10072001: Tank-binding kinase inhibitor compounds
2-(oxan-4-yloxy)-5-[2-(4-piperazin-1-ylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]benzonitrile	IC50	0.81 nM	US-10072001: Tank-binding kinase inhibitor compounds
2-[1-(2-hydroxyacetyl)piperidin-4-yl]oxy-5-[8-[4-(4-methylpiperazin-1-yl)phenyl]-7H-purin-6-yl]benzonitrile	IC50	0.815 nM	US-10072001: Tank-binding kinase inhibitor compounds
[4-[1-[2-[[6-(6-pyrrolidin-1-ylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-[1-(trifluoromethyl)cyclopropyl]methanone	IC50	0.819 nM	US-10894784: Heteroarylbenzimidazole compounds
[4-[1-[2-[[6-[6-[3-(trifluoromethyl)azetidin-1-yl]pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-[1-(trifluoromethyl)cyclopropyl]methanone	IC50	0.832 nM	US-10894784: Heteroarylbenzimidazole compounds
2-[1-(2-hydroxyacetyl)piperidin-4-yl]oxy-5-[6-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]benzonitrile	IC50	0.851 nM	US-10072001: Tank-binding kinase inhibitor compounds
(2,2-difluoro-1-methylcyclopropyl)-[4-[1-[2-[[6-(6-pyrrolidin-1-ylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]methanone	IC50	0.86 nM	US-10894784: Heteroarylbenzimidazole compounds
1-[4-[1-[2-[[4-chloro-5-[1-[(2,2-difluorocyclopropyl)methyl]pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-3,3,3-trifluoropropan-1-one	IC50	0.88 nM	US-10894784: Heteroarylbenzimidazole compounds
[4-[1-[2-[[4-chloro-5-[1-(cyclobutylmethyl)pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-cyclopropylmethanone	IC50	0.88 nM	US-10894784: Heteroarylbenzimidazole compounds
3,3,3-trifluoro-1-[4-[1-[2-[[6-[6-[3-(trifluoromethyl)azetidin-1-yl]pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]propan-1-one	IC50	0.943 nM	US-10894784: Heteroarylbenzimidazole compounds
2-(oxan-4-yloxy)-5-[2-[(4-piperidin-4-yl-2-pyridinyl)amino]-4-pyridinyl]benzonitrile	IC50	1 nM	US-8969335: Benzonitrile derivatives as kinase inhibitors
5-(4-((3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
5-(4-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
5-(4-((4-(piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile, trifluoroacetic acid salt	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((S)-3,3-difluoro-1-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-(1H-1,2,3-triazole-5-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-(4H-1,2,4-triazole-3-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-(1H-pyrazole-5-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-(1H-imidazole-5-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-(1-methyl-1H-1,2,3-triazole-4-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-((3,3-difluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
(R)-2-((3,3-difluoro-1-(2- hydroxyacetyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-1- yl)phenyl)amino)-1,3,5- triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((S)-3,3-difluoro-1-((S)-2- hydroxypropanoyl)piperidin- 4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1,3,5- triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
(S)-2-((3,3-difluoro-1-(1H-pyrazole-5-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
(S)-2-((3,3-difluoro-1-(1H-1,2,3-triazole-5-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((4R,5S)-5-fluoro-1-(2- hydroxyacetyl)-3,3- dimethylpiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-1- yl)phenyl)amino)-1,3,5- triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-((R)-2-(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-((S)-2-(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-((S)-2-(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds
2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-((S)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile	IC50	1 nM	US-10253019: Tank-binding kinase inhibitor compounds

ChEMBL bioactivities

2665 potent at pChembl≥5 of 2864 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.22	IC50	0.06	nM	CHEMBL3604928
9.48	IC50	0.33	nM	CHEMBL5743492
9.32	IC50	0.48	nM	CHEMBL5985679
9.32	IC50	0.473	nM	CHEMBL6002719
9.31	IC50	0.49	nM	CHEMBL5742193
9.30	IC50	0.503	nM	CHEMBL5976946
9.25	IC50	0.564	nM	CHEMBL5758899
9.25	IC50	0.558	nM	CHEMBL5955330
9.25	IC50	0.566	nM	CHEMBL5969068
9.21	IC50	0.61	nM	CHEMBL5758899
9.21	IC50	0.62	nM	CHEMBL5815915
9.19	IC50	0.644	nM	CHEMBL5826826
9.19	IC50	0.64	nM	CHEMBL5840596
9.18	IC50	0.66	nM	CHEMBL5758899
9.15	IC50	0.7	nM	CHEMBL4566796
9.15	IC50	0.7	nM	CHEMBL5795732
9.14	IC50	0.72	nM	CHEMBL5752148
9.14	IC50	0.73	nM	CHEMBL6055301
9.12	IC50	0.763	nM	CHEMBL5839714
9.12	IC50	0.762	nM	CHEMBL5892587
9.12	IC50	0.76	nM	CHEMBL6008205
9.12	IC50	0.76	nM	CHEMBL5747287
9.10	IC50	0.8	nM	CHEMBL5413962
9.09	IC50	0.821	nM	CHEMBL6017702
9.09	IC50	0.819	nM	CHEMBL5765209
9.08	IC50	0.832	nM	CHEMBL5906962
9.07	IC50	0.849	nM	CHEMBL5880587
9.07	IC50	0.86	nM	CHEMBL5744264
9.06	IC50	0.87	nM	CHEMBL6052607
9.06	IC50	0.88	nM	CHEMBL5842684
9.06	IC50	0.88	nM	CHEMBL5849082
9.05	IC50	0.9	nM	CHEMBL5818276
9.05	IC50	0.9	nM	CHEMBL5914403
9.05	IC50	0.883	nM	CHEMBL5845990
9.05	Kd	0.89	nM	STAUROSPORINE
9.04	IC50	0.91	nM	CHEMBL6026197
9.04	IC50	0.91	nM	CHEMBL5848650
9.03	IC50	0.943	nM	CHEMBL5779563
9.02	IC50	0.96	nM	CHEMBL5803178
9.00	IC50	1	nM	CHEMBL3650697
9.00	IC50	1	nM	CHEMBL4435393
9.00	IC50	1	nM	CHEMBL5920268
9.00	IC50	1.01	nM	CHEMBL6062742
9.00	IC50	1	nM	CHEMBL5843260
9.00	IC50	1	nM	CHEMBL5757233
9.00	IC50	1	nM	CHEMBL5933597
8.99	IC50	1.02	nM	CHEMBL5982478
8.99	IC50	1.02	nM	CHEMBL5843698
8.98	IC50	1.05	nM	CHEMBL6046235
8.97	IC50	1.06	nM	CHEMBL5752148

PubChem BioAssay actives

513 with measured affinity, of 1843 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-(4-nitrophenoxy)pyrimidin-4-amine	1575498: Inhibition of TBK1 (unknown origin) using biotinylated peptide as substrate preincubated for 30 mins by fluorescence activity-based assay	ic50	0.0001	uM
3,3,3-trifluoro-1-[4-[(1R)-1-[2-[[6-[6-(methoxymethyl)pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]propan-1-one	1582160: Inhibition of recombinant full length human N-terminal His-tagged TBK1 using biotin-labelled Ahx-GDEDFSSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.0007	uM
3-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)-5-(3-methylsulfonylphenyl)-2H-pyrazolo[3,4-b]pyridine	1978806: Inhibition of GST-tagged human full-length recombinant TBK1 incubated for 1 hr in presence of ATP by Z’-Lyte based assay	ic50	0.0008	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	625072: Binding constant for TBK1 kinase domain	kd	0.0009	uM
1-[4-[(1R)-1-[2-[[6-[1-(cyclopropylmethyl)pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-3,3,3-trifluoropropan-1-one	1582160: Inhibition of recombinant full length human N-terminal His-tagged TBK1 using biotin-labelled Ahx-GDEDFSSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.0010	uM
5-[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]pyrimidin-4-yl]-2-pyrrolidin-1-ylbenzonitrile	1575517: Inhibition of TBK1 (unknown origin)	ic50	0.0010	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637142: Inhibition of full-length recombinant human GST-tagged TBK1 expressed in insect cells by Z’-LYTE assay	ic50	0.0010	uM
1-[(3-hydroxyphenyl)methyl]-3-(4-pyridin-4-yl-1,3-thiazol-2-yl)urea;methanesulfonic acid	1119794: Inhibition of TBK1 (unknown origin)	ic50	0.0010	uM
methyl (15S,16S)-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-16-carboxylate	1801133: KinEASE-STK Assay from Article 10.1021/cb500908d: “Identification and further development of potent TBK1 inhibitors.”	ic50	0.0010	uM
(2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1388077: Inhibition of TBK1 (unknown origin)	ic50	0.0013	uM
N-[3-[[5-bromo-2-(4-ethoxyanilino)pyrimidin-4-yl]amino]propyl]-N-methylcyclobutanecarboxamide	1388068: Binding affinity to human full length wild-type TBK1 expressed in mammalian expression system	kd	0.0013	uM
3,3,3-trifluoro-1-[4-[(1R)-1-[2-[[6-(6-methylpyrimidin-4-yl)-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]propan-1-one	1582160: Inhibition of recombinant full length human N-terminal His-tagged TBK1 using biotin-labelled Ahx-GDEDFSSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.0020	uM
1-[4-[(1R)-1-[2-[[6-[6-(dimethylamino)pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-3,3,3-trifluoropropan-1-one	1582160: Inhibition of recombinant full length human N-terminal His-tagged TBK1 using biotin-labelled Ahx-GDEDFSSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.0020	uM
3,3,3-trifluoro-1-[4-[(1R)-1-[2-[[6-(5-propan-2-yloxypyrimidin-4-yl)-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]propan-1-one	1582160: Inhibition of recombinant full length human N-terminal His-tagged TBK1 using biotin-labelled Ahx-GDEDFSSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.0020	uM
1-[4-[(1R)-1-[2-[[6-[1-(cyclobutylmethyl)pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-3,3,3-trifluoropropan-1-one	1582160: Inhibition of recombinant full length human N-terminal His-tagged TBK1 using biotin-labelled Ahx-GDEDFSSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.0020	uM
1-[4-[(1R)-1-[2-[[6-[6-(cyclopropylmethoxy)pyrimidin-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]ethyl]piperazin-1-yl]-3,3,3-trifluoropropan-1-one	1582160: Inhibition of recombinant full length human N-terminal His-tagged TBK1 using biotin-labelled Ahx-GDEDFSSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.0020	uM
N-[3-[[5-cyclopropyl-2-[[1-(oxan-4-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0020	uM
N-[3-[[5-bromo-2-(3-fluoroanilino)pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0020	uM
N-[3-[[2-[(1-cyclobutylpyrazol-4-yl)amino]-5-cyclopropylpyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0020	uM
N-[3-[[5-cyclopropyl-2-[4-(4-methylpiperazine-1-carbonyl)anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0020	uM
(3Z)-4-[(3S)-3-hydroxypyrrolidin-1-yl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-5-nitro-1H-indol-2-one	1801133: KinEASE-STK Assay from Article 10.1021/cb500908d: “Identification and further development of potent TBK1 inhibitors.”	ic50	0.0030	uM
N-[3-[[5-cyclopropyl-2-[3-(1,2,4-triazol-1-ylmethyl)anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0030	uM
N-[3-[[5-cyclopropyl-2-[4-(1,2,4-triazol-1-yl)anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0030	uM
N-[3-[[2-(3-aminophenyl)-6-bromo-1H-imidazo[4,5-b]pyridin-7-yl]amino]propyl]cyclobutanecarboxamide	654913: Inhibition of recombinant TBK1 using 5FAM-AhxKRRAL(ps)VASLPGL as substrate by microfluidic mobility shift assay	ic50	0.0030	uM
(2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]-5-iodopyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1388068: Binding affinity to human full length wild-type TBK1 expressed in mammalian expression system	kd	0.0040	uM
N-[3-[[5-cyclopropyl-2-[(1-propan-2-ylpyrazol-4-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0040	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide	1993895: Inhibition of TBK1 (unknown origin)	ic50	0.0040	uM
N-[3-[[6-bromo-2-[4-(2-piperidin-1-ylethoxy)phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]propyl]cyclobutanecarboxamide	654913: Inhibition of recombinant TBK1 using 5FAM-AhxKRRAL(ps)VASLPGL as substrate by microfluidic mobility shift assay	ic50	0.0040	uM
7-[3-(cyclobutanecarbonylamino)propylamino]-2-[4-(2-piperidin-1-ylethoxy)phenyl]-1H-imidazo[4,5-b]pyridine-6-carboxamide	654913: Inhibition of recombinant TBK1 using 5FAM-AhxKRRAL(ps)VASLPGL as substrate by microfluidic mobility shift assay	ic50	0.0040	uM
1-(aminomethyl)-N-[3-[[6-bromo-2-(4-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-7-yl]amino]propyl]cyclopropane-1-carboxamide	654913: Inhibition of recombinant TBK1 using 5FAM-AhxKRRAL(ps)VASLPGL as substrate by microfluidic mobility shift assay	ic50	0.0040	uM
N-[3-[[6-bromo-2-(4-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-7-yl]amino]propyl]cyclobutanecarboxamide	1075341: Inhibition of recombinant full-length TBK1 (unknown origin) using CK1tide as substrate by microfluidic mobility shift assay	ic50	0.0040	uM
N-[3-[[2-[(1-cyclopentylpyrazol-4-yl)amino]-5-cyclopropylpyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0040	uM
1-[4-[[2-[[6-[1-(cyclopropylmethyl)pyrazol-4-yl]-1H-benzimidazol-2-yl]amino]-4-pyridinyl]methyl]piperazin-1-yl]-3,3,3-trifluoropropan-1-one	1582160: Inhibition of recombinant full length human N-terminal His-tagged TBK1 using biotin-labelled Ahx-GDEDFSSFAEPG peptide as substrate preincubated with enzyme for 15 mins followed by substrate addition and further incubated for 30 mins in presence of 10 uM of ATP by TR-FRET assay	ic50	0.0050	uM
7-[2-[3-(cyclohexanecarbonylamino)propyl]hydrazinyl]-2-[4-(4-methoxyphenyl)phenyl]-1H-imidazo[4,5-b]pyridine-6-carboxamide	1575517: Inhibition of TBK1 (unknown origin)	ic50	0.0050	uM
N-[3-[[6-bromo-2-(4-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-7-yl]amino]propyl]-N-methylcyclobutanecarboxamide	654913: Inhibition of recombinant TBK1 using 5FAM-AhxKRRAL(ps)VASLPGL as substrate by microfluidic mobility shift assay	ic50	0.0050	uM
(2S,4S)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1388068: Binding affinity to human full length wild-type TBK1 expressed in mammalian expression system	kd	0.0059	uM
N-[3-[[5-iodo-4-[3-(thiophene-2-carbonylamino)propylamino]pyrimidin-2-yl]amino]phenyl]pyrrolidine-1-carboxamide	1575515: Competitive inhibition of TBK1 (unknown origin) by immunoprecipitation method	ic50	0.0060	uM
N-[3-[[5-bromo-4-[3-(thiophene-2-carbonylamino)propylamino]pyrimidin-2-yl]amino]phenyl]pyrrolidine-1-carboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0060	uM
N-[3-[[5-cyclopropyl-2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0060	uM
N-[3-[[5-cyclopropyl-2-[4-[(dimethylamino)methyl]anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0060	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	1575498: Inhibition of TBK1 (unknown origin) using biotinylated peptide as substrate preincubated for 30 mins by fluorescence activity-based assay	ic50	0.0062	uM
N-[3-[[5-cyclopropyl-2-[[1-(1-propan-2-ylpiperidin-4-yl)pyrazol-4-yl]amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0070	uM
N-[3-[[6-bromo-2-(4-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-7-yl]amino]propyl]-2,2-dimethylpropanamide	654913: Inhibition of recombinant TBK1 using 5FAM-AhxKRRAL(ps)VASLPGL as substrate by microfluidic mobility shift assay	ic50	0.0070	uM
N-[3-[[5-cyclopropyl-2-[(2-cyclopropyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0070	uM
N-[3-[[5-cyclopropyl-2-[(1-ethylpyrazol-4-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0070	uM
N-[3-[[5-cyclopropyl-2-[(1,3-dimethylindazol-6-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0070	uM
2-[7-[3-(cyclopentanecarbonylamino)propylamino]-2-(4-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-6-yl]-1,3-thiazole-4-carboxamide	1075337: Inhibition of TBK1 in HEK293 cells after 4.5 hrs by ISRE-luciferase reporter gene assay in presence of poly I:C	ic50	0.0070	uM
N-[3-[[5-cyclopropyl-2-(3-fluoroanilino)pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0080	uM
N-[3-[[5-cyclopropyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0080	uM
N-[3-[[5-cyclopropyl-2-[4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	718696: Inhibition of TBK1 by radiometry	ic50	0.0080	uM

CTD chemical–gene interactions

59 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	3
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
aristolochic acid I	decreases expression	1
PAM2-CSK4	increases phosphorylation	1
dicrotophos	decreases expression	1
2-anisidine	decreases expression	1
oxybenzone	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
eriodictyol	decreases activity	1
beryllium sulfate	increases phosphorylation, increases reaction	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
chrysin	decreases activity	1
amlexanox	decreases activity	1
esculentoside A	increases phosphorylation	1
perfluorooctane sulfonic acid	decreases expression	1
JHW 015	decreases reaction, increases phosphorylation	1
1,1-dimethylbutyl-1-deoxy-Delta(9)-THC	increases phosphorylation, decreases reaction	1
lipopolysaccharide, E coli O55-B5	increases phosphorylation	1
3,5-bis(2-fluorobenzylidene)piperidin-4-one	decreases reaction, increases expression	1
CpG ODN 2216	decreases reaction, increases phosphorylation	1
STA 9090	decreases expression	1
asparanin A	decreases expression	1
jinfukang	decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
BX795	decreases activity	1
Resveratrol	decreases reaction, increases expression	1
Acetaminophen	decreases expression	1
Glyphosate	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1

ChEMBL screening assays

475 unique, capped per target: 473 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1942749	Binding	Inhibition of human IKKepsilon/TBK1 in HL-60 cells lysate assessed as reduction of labeling of acyl-phosphate ATP probe at 100 nM	6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3β: discovery of nitrile derivatives with picomolar potency. — Bioorg Med Chem Lett
CHEMBL1963698	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: TBK1	PubChem BioAssay data set

Cellosaurus cell lines

24 cell lines: 17 cancer cell line, 6 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A6LQ	U2OS TBK1 KO	Cancer cell line	Female
CVCL_A8AY	THP1-Dual KO-TBK1	Cancer cell line	Male
CVCL_B7ZT	Abcam Raji TBK1 KO	Cancer cell line	Male
CVCL_C0AL	Abcam THP-1 TBK1 KO	Cancer cell line	Male
CVCL_C2VR	HeLa S3 penta KO-TBK1 KO	Cancer cell line	Female
CVCL_C2VT	HeLa S3 penta KO-TBK1/ULK1/ULK2 TKO	Cancer cell line	Female
CVCL_C7C9	Abcam PC-3 TBK1 KO	Cancer cell line	Male
CVCL_D7ES	HeLa M TBK1-KO	Cancer cell line	Female
CVCL_D7EU	HeLa M TBK1-KO + RAB7-KO	Cancer cell line	Female
CVCL_D7EV	HeLa M TBK1-KO + TBK1-E696K-GFP	Cancer cell line	Female

Clinical trials (associated diseases)

104 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT01951924	PHASE3	COMPLETED	LIME Study (LFB IVIg MMN Efficacy Study)
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT00076687	PHASE2	COMPLETED	Safety Study of Botulinum Toxin Type A in Post-Upper Limb Stroke Patients With Reduced Lung Function
NCT00324454	PHASE2	COMPLETED	Levetiracetam for Cramps, Spasticity and Neuroprotection in Motor Neuron Disease
NCT02469896	PHASE2	COMPLETED	A Trial of Tocilizumab in ALS Subjects
NCT03114215	PHASE2	COMPLETED	Effect of MD1003 in Amyotrophic Lateral Sclerosis
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03196375	PHASE2	TERMINATED	A Study to Assess FLX-787 in Subjects With Motor Neuron Disease Experiencing Muscle Cramps.
NCT03508453	PHASE2	WITHDRAWN	IC14 for Treatment of Amyotrophic Lateral Sclerosis
NCT03705390	PHASE2	TERMINATED	A Safety and Tolerability Study of ILB® in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT04579666	PHASE2	TERMINATED	MERIDIAN: A Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Adults With Amyotrophic Lateral Sclerosis (ALS)
NCT04788745	PHASE2	COMPLETED	Targeting Metabolic Flexibility in Amyotrophic Lateral Sclerosis (ALS)
NCT06315608	PHASE2	NOT_YET_RECRUITING	MRG-001 in Patients With Amyotrophic Lateral Sclerosis
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT02870634	PHASE1	COMPLETED	Phase 1 Dose Escalation and PK Study of Cu(II)ATSM in ALS/MND
NCT02987413	PHASE1	COMPLETED	Escalated Application of Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis Patients
NCT03487263	PHASE1	COMPLETED	Dose-Escalation, Safety and Pharmacokinetic Study of IC14 in Motor Neurone Disease
NCT03929068	PHASE1	COMPLETED	Sinemet for Spasticity and Function in Amyotrophic Lateral Sclerosis and Primary Lateral Sclerosis
NCT04894240	PHASE1	COMPLETED	A Study of Monepantel in Individuals With Motor Neurone Disease
NCT06177431	PHASE1	COMPLETED	An Open Label Extension Study of Monepantel in Individuals With Motor Neurone Disease
NCT07093268	PHASE1	NOT_YET_RECRUITING	Safety of Intrathecal Riluzole in Patients With Amyotrophic Lateral Sclerosis
NCT07204977	PHASE1	ACTIVE_NOT_RECRUITING	Acamprosate in C9orf72 Hexanucleotide Repeat Expansion Amyotrophic Lateral Sclerosis (ACALS)
NCT01776970	PHASE2/PHASE3	COMPLETED	Safety and Efficacy on Spasticity Symptoms of a Cannabis Sativa Extract in Motor Neuron Disease
NCT00956488	PHASE1/PHASE2	COMPLETED	Supported Treadmill Ambulation Training (STAT) for Patients Diagnosed With Amyotrophic Lateral Aclerosis
NCT01369901	PHASE1/PHASE2	COMPLETED	Effect of Functional Exercise in Patients With Spinal Bulbar Muscular Atrophy
NCT03067857	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Therapy for Motor Neuron Disease
NCT07396818	PHASE1/PHASE2	NOT_YET_RECRUITING	Kamlanoflast In Amyotrophic Lateral Sclerosis
NCT00001220	Not specified	COMPLETED	Ultrasound and Videofluoroscopy for Diagnosing Swallowing Disorders
NCT00001780	Not specified	COMPLETED	Magnetic Stimulation of the Human Nervous System
NCT00004568	Not specified	RECRUITING	Study of Inherited Neurological Disorders
NCT00071435	Not specified	COMPLETED	Brain Function in Primary Lateral Sclerosis
NCT00362362	Not specified	COMPLETED	Collection of Blood Samples for DNA in Motor Neuron Disease
NCT00537446	Not specified	TERMINATED	Effect of Noninvasive Ventilation on Lung Function in Amyotrophic Lateral Sclerosis
NCT00537641	Not specified	COMPLETED	Efficacy of Noninvasive Ventilation in Amyotrophic Lateral Sclerosis (ALS)
NCT00714636	Not specified	COMPLETED	Cerebrospinal Fluid Repository
NCT00716131	Not specified	COMPLETED	Amyotrophic Lateral Sclerosis (ALS) Tissue Donation Program
NCT00718003	Not specified	TERMINATED	Noninvasive Examination of the Work of Breathing in Patients With Amyotrophic Lateral Sclerosis (ALS).
NCT00718016	Not specified	TERMINATED	Assessment of the Cyberlink Control System for Use by the Amyotrophic Lateral Sclerosis (ALS) Patient
NCT00718107	Not specified	TERMINATED	Satisfaction Survey for Amyotrophic Lateral Sclerosis (ALS) Patients Comparing Rooms With and Without Assistive Technology