Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8DXMS3)

• DOT Name: Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2)
• Synonyms: EC 2.7.11.1; Eukaryotic translation initiation factor 2-alpha kinase 2; eIF-2A protein kinase 2; Interferon-inducible RNA-dependent protein kinase; P1/eIF-2A protein kinase; Protein kinase RNA-activated; PKR; Protein kinase R; Tyrosine-protein kinase EIF2AK2; EC 2.7.10.2; p68 kinase
• Gene Name: EIF2AK2
• Related Disease:
  Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome
  Early-onset generalized limb-onset dystonia
  Dystonia 33
• UniProt ID: E2AK2_HUMAN
• PDB ID: 1QU6; 2A19; 2A1A; 3UIU; 6D3K; 6D3L; 7OBK; 7OBL; 8BI7; 8I9J
• EC Number: 2.7.10.2; 2.7.11.1
• Pfam ID: PF00035 ; PF00069
• Sequence:
  MAGDLSAGFFMEELNTYRQKQGVVLKYQELPNSGPPHDRRFTFQVIIDGREFPEGEGRSK
  KEAKNAAAKLAVEILNKEKKAVSPLLLTTTNSSEGLSMGNYIGLINRIAQKKRLTVNYEQ
  CASGVHGPEGFHYKCKMGQKEYSIGTGSTKQEAKQLAAKLAYLQILSEETSVKSDYLSSG
  SFATTCESQSNSLVTSTLASESSSEGDFSADTSEINSNSDSLNSSSLLMNGLRNNQRKAK
  RSLAPRFDLPDMKETKYTVDKRFGMDFKEIELIGSGGFGQVFKAKHRIDGKTYVIKRVKY
  NNEKAEREVKALAKLDHVNIVHYNGCWDGFDYDPETSDDSLESSDYDPENSKNSSRSKTK
  CLFIQMEFCDKGTLEQWIEKRRGEKLDKVLALELFEQITKGVDYIHSKKLIHRDLKPSNI
  FLVDTKQVKIGDFGLVTSLKNDGKRTRSKGTLRYMSPEQISSQDYGKEVDLYALGLILAE
  LLHVCDTAFETSKFFTDLRDGIISDIFDKKEKTLLQKLLSKKPEDRPNTSEILRTLTVWK
  KSPEKNERHTC
• Function: IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection. Inhibits viral replication via the integrated stress response (ISR): EIF2S1/eIF-2-alpha phosphorylation in response to viral infection converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting to a shutdown of cellular and viral protein synthesis, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4. 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). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: 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 proteasomal 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 pro-inflammatory 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. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin.
• Tissue Specificity: Highly expressed in thymus, spleen and bone marrow compared to non-hematopoietic tissues such as small intestine, liver, or kidney tissues. Colocalizes with GSK3B and TAU in the Alzheimer disease (AD) brain. Elevated levels seen in breast and colon carcinomas, and which correlates with tumor progression and invasiveness or risk of progression.
• KEGG Pathway:
  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)
  Coro.virus disease - COVID-19 (hsa05171)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Inhibition of PKR (R-HSA-169131)
  SUMOylation of immune response proteins (R-HSA-4755510)
  Interferon alpha/beta signaling (R-HSA-909733)
  PKR-mediated signaling (R-HSA-9833482)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome	DIS682TW	Strong	Autosomal dominant	[1]
Early-onset generalized limb-onset dystonia	DISDY57E	Supportive	Autosomal dominant	[2]
Dystonia 33	DISTOV9T	Limited	Unknown	[2]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[15]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[16]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[17]
Interferon alfa-2B	DMWCQP4	Approved	Interferon alfa-2B increases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[22]
Staurosporine	DM0E9BR	Investigative	Staurosporine decreases the activity of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[24]

6 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the phosphorylation of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[21]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2).	[23]

References

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• [13] Musashi-1 promotes chemoresistant granule formation by PKR/eIF2 signalling cascade in refractory glioblastoma. Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1850-1861. doi: 10.1016/j.bbadis.2018.02.017. Epub 2018 Feb 24.
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