Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4SPU0U)

• DOT Name: Gamma-interferon-inducible protein 16 (IFI16)
• Synonyms: Ifi-16; Interferon-inducible myeloid differentiation transcriptional activator
• Gene Name: IFI16
• Related Disease:
  Neoplasm
  Autoimmune disease
  Behcet disease
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Chikungunya virus infection
  Chondrosarcoma
  Chronic hepatitis B virus infection
  Cystic fibrosis
  Cytomegalovirus infection
  Head-neck squamous cell carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Herpes simplex infection
  HIV infectious disease
  Inflammatory bowel disease
  Isolated congenital microcephaly
  Osteosarcoma
  Periodontal disease
  Progressive multifocal leukoencephalopathy
  Prostate neoplasm
  Psoriasis
  Psoriatic arthritis
  Scleroderma
  Sjogren syndrome
  Squamous cell carcinoma
  Systemic sclerosis
  Tuberculosis
  Wilms tumor
  Zika virus infection
  Advanced cancer
  Immune system disorder
  Lupus
  Human papillomavirus infection
  Human T-lymphotropic virus 1 infectious disease
  Kaposi sarcoma
  Metastatic malignant neoplasm
  Rheumatoid arthritis
  Prostate cancer
  Prostate carcinoma
  Small lymphocytic lymphoma
  Systemic lupus erythematosus
• UniProt ID: IF16_HUMAN
• PDB ID: 2OQ0; 3B6Y; 3RLN; 3RLO; 3RNU; 4QGU
• Pfam ID: PF02760 ; PF02758
• Sequence:
  MGKKYKNIVLLKGLEVINDYHFRMVKSLLSNDLKLNLKMREEYDKIQIADLMEEKFRGDA
  GLGKLIKIFEDIPTLEDLAETLKKEKLKVKGPALSRKRKKEVDATSPAPSTSSTVKTEGA
  EATPGAQKRKKSTKEKAGPKGSKVSEEQTQPPSPAGAGMSTAMGRSPSPKTSLSAPPNSS
  STENPKTVAKCQVTPRRNVLQKRPVIVKVLSTTKPFEYETPEMEKKIMFHATVATQTQFF
  HVKVLNTSLKEKFNGKKIIIISDYLEYDSLLEVNEESTVSEAGPNQTFEVPNKIINRAKE
  TLKIDILHKQASGNIVYGVFMLHKKTVNQKTTIYEIQDDRGKMDVVGTGQCHNIPCEEGD
  KLQLFCFRLRKKNQMSKLISEMHSFIQIKKKTNPRNNDPKSMKLPQEQRQLPYPSEASTT
  FPESHLRTPQMPPTTPSSSFFTKKSEDTISKMNDFMRMQILKEGSHFPGPFMTSIGPAES
  HPHTPQMPPSTPSSSFLTTKSEDTISKMNDFMRMQILKEGSHFPGPFMTSIGPAESHPHT
  PQMPPSTPSSSFLTTLKPRLKTEPEEVSIEDSAQSDLKEVMVLNATESFVYEPKEQKKMF
  HATVATENEVFRVKVFNIDLKEKFTPKKIIAIANYVCRNGFLEVYPFTLVADVNADRNME
  IPKGLIRSASVTPKINQLCSQTKGSFVNGVFEVHKKNVRGEFTYYEIQDNTGKMEVVVHG
  RLTTINCEEGDKLKLTCFELAPKSGNTGELRSVIHSHIKVIKTRKNKKDILNPDSSMETS
  PDFFF
• Function: Binds double-stranded DNA. Binds preferentially to supercoiled DNA and cruciform DNA structures. Seems to be involved in transcriptional regulation. May function as a transcriptional repressor. Could have a role in the regulation of hematopoietic differentiation through activation of unknown target genes. Controls cellular proliferation by modulating the functions of cell cycle regulatory factors including p53/TP53 and the retinoblastoma protein. May be involved in TP53-mediated transcriptional activation by enhancing TP53 sequence-specific DNA binding and modulating TP53 phosphorylation status. Seems to be involved in energy-level-dependent activation of the ATM/ AMPK/TP53 pathway coupled to regulation of autophagy. May be involved in regulation of TP53-mediated cell death also involving BRCA1. May be involved in the senescence of prostate epithelial cells. Involved in innate immune response by recognizing viral dsDNA in the cytosol and probably in the nucleus. After binding to viral DNA in the cytoplasm recruits TMEM173/STING and mediates the induction of IFN-beta. Has anti-inflammatory activity and inhibits the activation of the AIM2 inflammasome, probably via association with AIM2. Proposed to bind viral DNA in the nucleus, such as of Kaposi's sarcoma-associated herpesvirus, and to induce the formation of nuclear caspase-1-activating inflammasome formation via association with PYCARD. Inhibits replication of herpesviruses such as human cytomegalovirus (HCMV) probably by interfering with promoter recruitment of members of the Sp1 family of transcription factors. Necessary to activate the IRF3 signaling cascade during human herpes simplex virus 1 (HHV-1) infection and promotes the assembly of heterochromatin on herpesviral DNA and inhibition of viral immediate-early gene expression and replication. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer; [Isoform IFI16-beta]: Isoform that specifically inhibits the AIM2 inflammasome. Binds double-stranded DNA (dsDNA) in the cytoplasm, impeding its detection by AIM2. Also prevents the interaction between AIM2 and PYCARD/ASC via its interaction with AIM2, thereby inhibiting assembly of the AIM2 inflammasome. This isoform also weakly induce production of type I interferon-beta (IFNB1) via its interaction with STING1.
• Tissue Specificity: Expressed in peripheral blood leukocytes, fibroblasts and lymphoid cells. Present in myeloid precursors (CD34+) and throughout monocyte development, but its expression is down-regulated in erythroid and polymorphonuclear precursor cells. Present in prostate, ovary and breast (at protein level).; [Isoform IFI16-beta]: Widely expressed.
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  Cytosolic D.-sensing pathway (hsa04623)
• Reactome Pathway:
  IRF3-mediated induction of type I IFN (R-HSA-3270619)
  STING mediated induction of host immune responses (R-HSA-1834941)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Chikungunya virus infection	DISDXEHY	Strong	Altered Expression	[6]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[4]
Chronic hepatitis B virus infection	DISHL4NT	Strong	Biomarker	[7]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[8]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[9]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[1]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[12]
HIV infectious disease	DISO97HC	Strong	Biomarker	[13]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[14]
Isolated congenital microcephaly	DISUXHZ6	Strong	Altered Expression	[6]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[4]
Periodontal disease	DISJQHVN	Strong	Altered Expression	[15]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[16]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[17]
Psoriasis	DIS59VMN	Strong	Biomarker	[18]
Psoriatic arthritis	DISLWTG2	Strong	Biomarker	[18]
Scleroderma	DISVQ342	Strong	Biomarker	[19]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[20]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[21]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[19]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[22]
Wilms tumor	DISB6T16	Strong	Biomarker	[23]
Zika virus infection	DISQUCTY	Strong	Altered Expression	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[24]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[25]
Lupus	DISOKJWA	moderate	Biomarker	[26]
Human papillomavirus infection	DISX61LX	Disputed	Altered Expression	[1]
Human T-lymphotropic virus 1 infectious disease	DISN5C4M	Disputed	Biomarker	[27]
Kaposi sarcoma	DISC1H1Z	Disputed	Biomarker	[28]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Altered Expression	[1]
Rheumatoid arthritis	DISTSB4J	Disputed	Biomarker	[29]
Prostate cancer	DISF190Y	Limited	Altered Expression	[17]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[17]
Small lymphocytic lymphoma	DIS30POX	Limited	Altered Expression	[30]
Systemic lupus erythematosus	DISI1SZ7	Limited	Biomarker	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Gamma-interferon-inducible protein 16 (IFI16).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Gamma-interferon-inducible protein 16 (IFI16).	[49]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Gamma-interferon-inducible protein 16 (IFI16).	[50]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[36]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[37]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[38]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[39]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[40]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[41]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[42]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[33]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Gamma-interferon-inducible protein 16 (IFI16).	[43]
Marinol	DM70IK5	Approved	Marinol increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[44]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[42]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[45]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Gamma-interferon-inducible protein 16 (IFI16).	[46]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[47]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[48]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[42]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 decreases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[51]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[52]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[53]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[54]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[55]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[45]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Gamma-interferon-inducible protein 16 (IFI16).	[56]

References

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