Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTH5TC2)

• DTT Name: NF-kappa-B-activating kinase (TBK1)
• Synonyms: TANK-binding kinase 1; T2K; Serine/threonine-protein kinase TBK1; NAK
• Gene Name: TBK1
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Kinase
• UniProt ID: TBK1_HUMAN
• TTD ID: T63024
• EC Number: EC 2.7.11.1
• Sequence:
  MQSTSNHLWLLSDILGQGATANVFRGRHKKTGDLFAIKVFNNISFLRPVDVQMREFEVLK
  KLNHKNIVKLFAIEEETTTRHKVLIMEFCPCGSLYTVLEEPSNAYGLPESEFLIVLRDVV
  GGMNHLRENGIVHRDIKPGNIMRVIGEDGQSVYKLTDFGAARELEDDEQFVSLYGTEEYL
  HPDMYERAVLRKDHQKKYGATVDLWSIGVTFYHAATGSLPFRPFEGPRRNKEVMYKIITG
  KPSGAISGVQKAENGPIDWSGDMPVSCSLSRGLQVLLTPVLANILEADQEKCWGFDQFFA
  ETSDILHRMVIHVFSLQQMTAHKIYIHSYNTATIFHELVYKQTKIISSNQELIYEGRRLV
  LEPGRLAQHFPKTTEENPIFVVSREPLNTIGLIYEKISLPKVHPRYDLDGDASMAKAITG
  VVCYACRIASTLLLYQELMRKGIRWLIELIKDDYNETVHKKTEVVITLDFCIRNIEKTVK
  VYEKLMKINLEAAELGEISDIHTKLLRLSSSQGTIETSLQDIDSRLSPGGSLADAWAHQE
  GTHPKDRNVEKLQVLLNCMTEIYYQFKKDKAERRLAYNEEQIHKFDKQKLYYHATKAMTH
  FTDECVKKYEAFLNKSEEWIRKMLHLRKQLLSLTNQCFDIEEEVSKYQEYTNELQETLPQ
  KMFTASSGIKHTMTPIYPSSNTLVEMTLGMKKLKEEMEGVVKELAENNHILERFGSLTMD
  GGLRNVDCL
• Function: 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, TMEM173/STING 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 and activates AKT1. Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich 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. Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents.
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  Toll-like receptor signaling pathway (hsa04620)
  NOD-like receptor signaling pathway (hsa04621)
  RIG-I-like receptor signaling pathway (hsa04622)
  Cytosolic DNA-sensing pathway (hsa04623)
  IL-17 signaling pathway (hsa04657)
  Alcoholic liver disease (hsa04936)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
  Yersinia infection (hsa05135)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coronavirus disease - COVID-19 (hsa05171)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)
  Regulation of innate immune responses to cytosolic DNA (R-HSA-3134975)
  STAT6-mediated induction of chemokines (R-HSA-3249367)
  IRF3-mediated induction of type I IFN (R-HSA-3270619)
  Interleukin-37 signaling (R-HSA-9008059)
  TICAM1-dependent activation of IRF3/IRF7 (R-HSA-9013973)
  TRAF3-dependent IRF activation pathway (R-HSA-918233)
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon (R-HSA-936964)
  Potential therapeutics for SARS (R-HSA-9679191)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  IRF3 mediated activation of type 1 IFN (R-HSA-1606341)

Molecular Interaction Atlas (MIA) of This DTT

14 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminopyrimidine derivative 10	DM2TF64	N. A.	N. A.	Patented	[1]
Aminopyrimidine derivative 6	DMZF0DK	N. A.	N. A.	Patented	[1]
Aminopyrimidine derivative 7	DMW98RI	N. A.	N. A.	Patented	[1]
Aminopyrimidine derivative 8	DML83KW	N. A.	N. A.	Patented	[1]
Aminopyrimidine derivative 9	DM5VRXW	N. A.	N. A.	Patented	[1]
PMID26293650-Compound-34	DMHXT12	N. A.	N. A.	Patented	[1]
PMID26293650-Compound-35	DMPG8MF	N. A.	N. A.	Patented	[1]
Pyrimidinyl compound 1	DMYKHQ8	N. A.	N. A.	Patented	[1]
Pyrimidinyl compound 2	DM9TW5O	N. A.	N. A.	Patented	[1]
Pyrimidinyl compound 3	DMOE2FZ	N. A.	N. A.	Patented	[1]
Pyrimidinyl compound 4	DM53O9Y	N. A.	N. A.	Patented	[1]
Pyrimidinyl compound 5	DMCKBGM	N. A.	N. A.	Patented	[1]
Pyrimidinyl compound 6	DML2E8S	N. A.	N. A.	Patented	[1]
Pyrimidinyl compound 7	DMMYW2L	N. A.	N. A.	Patented	[1]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MRT67307	DMYRCHG	Discovery agent	N.A.	Investigative	[2]
PMID23099093C17d	DMWS7O9	Discovery agent	N.A.	Investigative	[3]

References

• [1] TBK1 inhibitors: a review of patent literature (2011 - 2014).Expert Opin Ther Pat. 2015;25(12):1385-96.
• [2] Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104.
• [3] Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKepsilon kinases. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7169-73.