Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTC97NF)

• DTT Name: TNFA messenger RNA (TNF mRNA)
• Synonyms: Tumour necrosis factor alpha (mRNA); Tumour necrosis factor (mRNA); Tumor necrosis factor ligand superfamily member 2 (mRNA); Tumor necrosis factor (mRNA); TNFalpha (mRNA); TNFSF2 (mRNA); TNFA (mRNA); TNF-alpha (mRNA); TNF-a (mRNA); TNF alpha (mRNA); Cachectin (mRNA)
• Gene Name: TNF
• DTT Type: Discontinued target; [1]
• BioChemical Class: mRNA target
• UniProt ID: TNFA_HUMAN
• TTD ID: T16486
• Sequence:
  MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTLFCLLHFGVIGPQR
  EEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELR
  DNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRE
  TPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL
• Function: It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective. Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line. Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance. Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR.
• KEGG Pathway:
  Antifolate resistance (hsa01523)
  MAPK signaling pathway (hsa04010)
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  NF-kappa B signaling pathway (hsa04064)
  Sphingolipid signaling pathway (hsa04071)
  mTOR signaling pathway (hsa04150)
  Apoptosis (hsa04210)
  Necroptosis (hsa04217)
  TGF-beta signaling pathway (hsa04350)
  Osteoclast differentiation (hsa04380)
  Antigen processing and presentation (hsa04612)
  Toll-like receptor signaling pathway (hsa04620)
  NOD-like receptor signaling pathway (hsa04621)
  RIG-I-like receptor signaling pathway (hsa04622)
  C-type lectin receptor signaling pathway (hsa04625)
  Hematopoietic cell lineage (hsa04640)
  Natural killer cell mediated cytotoxicity (hsa04650)
  IL-17 signaling pathway (hsa04657)
  T cell receptor signaling pathway (hsa04660)
  Fc epsilon RI signaling pathway (hsa04664)
  TNF signaling pathway (hsa04668)
  Adipocytokine signaling pathway (hsa04920)
  Type II diabetes mellitus (hsa04930)
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)
  AGE-RAGE signaling pathway in diabetic complications (hsa04933)
  Alcoholic liver disease (hsa04936)
  Type I diabetes mellitus (hsa04940)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Yersinia infection (hsa05135)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coronavirus disease - COVID-19 (hsa05171)
  Proteoglycans in cancer (hsa05205)
  Asthma (hsa05310)
  Inflammatory bowel disease (hsa05321)
  Systemic lupus erythematosus (hsa05322)
  Rheumatoid arthritis (hsa05323)
  Allograft rejection (hsa05330)
  Graft-versus-host disease (hsa05332)
  Hypertrophic cardiomyopathy (hsa05410)
  Dilated cardiomyopathy (hsa05414)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NFkappaB signaling pathway (R-HSA-5357956)
  TNFR1-mediated ceramide production (R-HSA-5626978)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  Interleukin-10 signaling (R-HSA-6783783)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  TNF signaling (R-HSA-75893)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)

Molecular Interaction Atlas (MIA) of This DTT

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ISIS 104838	DMURWPH	Crohn disease	DD70	Discontinued in Phase 2	[1]
PNU-282987	DMGDC36	Schizophrenia	6A20	Terminated	[2]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Psoriasis	EA90	Skin	1.24E-17	0.42	1.18
Rheumatoid arthritis	FA20	Synovial tissue	7.38E-01	-0.07	-0.16

References

• [1] Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207.
• [2] Antisense oligonucleotide blockade of tumor necrosis factor-alpha in two murine models of colitis. J Pharmacol Exp Ther. 2003 Jan;304(1):411-24.