Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTXEZJ4)

• DTT Name: Tyrosine-protein kinase EIF2AK2 (p68)
• Synonyms: p68 kinase; Proteinkinase RNA-activated; Interferon-inducible RNA-dependent protein kinase p68; Interferon-induced, double-stranded RNA-activated protein kinase p68
• Gene Name: EIF2AK2
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Kinase
• UniProt ID: E2AK2_HUMAN
• TTD ID: T04831
• EC Number: EC 2.7.11.1
• Sequence:
  MAGDLSAGFFMEELNTYRQKQGVVLKYQELPNSGPPHDRRFTFQVIIDGREFPEGEGRSK
  KEAKNAAAKLAVEILNKEKKAVSPLLLTTTNSSEGLSMGNYIGLINRIAQKKRLTVNYEQ
  CASGVHGPEGFHYKCKMGQKEYSIGTGSTKQEAKQLAAKLAYLQILSEETSVKSDYLSSG
  SFATTCESQSNSLVTSTLASESSSEGDFSADTSEINSNSDSLNSSSLLMNGLRNNQRKAK
  RSLAPRFDLPDMKETKYTVDKRFGMDFKEIELIGSGGFGQVFKAKHRIDGKTYVIKRVKY
  NNEKAEREVKALAKLDHVNIVHYNGCWDGFDYDPETSDDSLESSDYDPENSKNSSRSKTK
  CLFIQMEFCDKGTLEQWIEKRRGEKLDKVLALELFEQITKGVDYIHSKKLIHRDLKPSNI
  FLVDTKQVKIGDFGLVTSLKNDGKRTRSKGTLRYMSPEQISSQDYGKEVDLYALGLILAE
  LLHVCDTAFETSKFFTDLRDGIISDIFDKKEKTLLQKLLSKKPEDRPNTSEILRTLTVWK
  KSPEKNERHTC
• Function: Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1). Inhibits viral replication via phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (EIF2S1), this phosphorylation impairs the recycling of EIF2S1 between successive rounds of initiation leading to inhibition of translation which eventually results in shutdown of cellular and viral protein synthesis. Also phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation. Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding proinflammatory cytokines and IFNs. Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6. Can act as both a positive and negative regulator of the insulin signaling pathway (ISP). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Can trigger apoptosis via FADD-mediated activation of CASP8. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin. IFN-induced dsRNA-dependent serine/threonine-protein kinase which plays a key role in the innate immune response to viral infection and is also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation.
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Necroptosis (hsa04217)
  Alzheimer disease (hsa05010)
  Hepatitis C (hsa05160)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Coronavirus disease - COVID-19 (hsa05171)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway: ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DTT

3 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
US9650366, 12	DMR3Z49	N. A.	N. A.	Patented	[2]
US9650366, 2	DM9HZ03	N. A.	N. A.	Patented	[2]
US9650366, 9	DMUCIPE	N. A.	N. A.	Patented	[2]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ASN-11124542	DMFNZOI	Discovery agent	N.A.	Investigative	[3]
indirubin derivative E804	DMFP1C5	Discovery agent	N.A.	Investigative	[1]
NU6140	DMCUSG3	Discovery agent	N.A.	Investigative	[1]

References

• [1] Identification of new inhibitors of protein kinase R guided by statistical modeling. Bioorg Med Chem Lett. 2011 Jul 1;21(13):4108-14.
• [2] Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors. US9650366.
• [3] Small molecule inhibitors of the RNA-dependent protein kinase. Biochem Biophys Res Commun. 2003 Aug 15;308(1):50-7.