Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTF8CQI)

• DTT Name: Tumor necrosis factor (TNF)
• Synonyms: Tumour necrosis factor alpha; Tumour necrosis factor; Tumor necrosis factor ligand superfamily member 2; TNFalpha; TNFSF2; TNFA; TNF-alpha; TNF-a; TNF alpha; Cachectin
• Gene Name: TNF
• DTT Type: Successful target; [1]
• Related Disease:
  Arterial occlusive disease [ICD-11: BD40]
  Multiple myeloma [ICD-11: 2A83]
  Pancreatitis [ICD-11: DC31-DC34]
  Psoriasis [ICD-11: EA90]
  Rheumatoid arthritis [ICD-11: FA20]
• BioChemical Class: Cytokine: tumor necrosis factor
• UniProt ID: TNFA_HUMAN
• TTD ID: T20178
• 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:
  MAPK signaling pathway (hsa04010)
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B signaling pathway (hsa04064)
  Sphingolipid signaling pathway (hsa04071)
  mTOR signaling pathway (hsa04150)
  Apoptosis (hsa04210)
  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)
  Hematopoietic cell lineage (hsa04640)
  Natural killer cell mediated cytotoxicity (hsa04650)
  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)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Type I diabetes mellitus (hsa04940)
  Alzheimer's disease (hsa05010)
  Amyotrophic lateral sclerosis (ALS) (hsa05014)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Leishmaniasis (hsa05140)
  Chagas disease (American trypanosomiasis) (hsa05142)
  African trypanosomiasis (hsa05143)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Influenza A (hsa05164)
  HTLV-I infection (hsa05166)
  Herpes simplex infection (hsa05168)
  Proteoglycans in cancer (hsa05205)
  Asthma (hsa05310)
  Inflammatory bowel disease (IBD) (hsa05321)
  Systemic lupus erythematosus (hsa05322)
  Rheumatoid arthritis (hsa05323)
  Allograft rejection (hsa05330)
  Graft-versus-host disease (hsa05332)
  Hypertrophic cardiomyopathy (HCM) (hsa05410)
  Dilated cardiomyopathy (hsa05414)
• 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)
  TNF signaling (R-HSA-75893)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)

Molecular Interaction Atlas (MIA) of This DTT

10 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Adalimumab	DMQMV1B	Rheumatoid arthritis	FA20	Approved	[1]
Certolizumab	DM5CL9Z	Rheumatoid arthritis	FA20	Approved	[2]
Enbrel	DM7RNP3	Arthritis	FA20	Approved	[3]
Etanercept	DMCV109	Arthritis	FA20	Approved	[4], [5]
Golimumab	DMHZV7X	Rheumatoid arthritis	FA20	Approved	[6], [7]
Infliximab	DMH7OIA	Plaque psoriasis	EA90.0	Approved	[8]
Lenalidomide	DM6Q7U4	Multiple myeloma	2A83	Approved	[9], [10]
Nafamostat	DMU1XOD	Pancreatitis	DC31-DC34	Approved	[11]
Pentoxifylline	DMU3DNC	Intermittent claudication	BD40.00	Approved	[12], [13]
Thalidomide	DM70BU5	Multiple myeloma	2A83	Approved	[14]

24 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABP 501	DM2J4YB	Rheumatoid arthritis	FA20	Phase 3	[15]
CPL-7075	DM62E7C	Diffuse systemic sclerosis	4A42.1	Phase 3	[16]
Golnerminogene pradenovac	DMKWV4B	Esophageal cancer	2B70	Phase 3	[17]
PF-06410293	DM2GF14	Rheumatoid arthritis	FA20	Phase 3	[18]
PF-06438179	DMM4C95	Rheumatoid arthritis	FA20	Phase 3	[19]
ABT-122	DM23UQ9	Psoriatic arthritis	FA21	Phase 2	[20]
AN0128	DMT3S10	Atopic dermatitis	EA80	Phase 2	[21], [22], [23]
AP-301-IH	DM3ICYL	Pneumonia	CA40	Phase 2	[24]
BAICALEIN	DM4C7E6	Influenza virus infection	1E30-1E32	Phase 2	[25]
DLX-105	DMDJUWG	Osteoarthritis	FA00-FA05	Phase 2	[26]
ESBA-105	DMYZWDC	Ocular disease	1F00.1Z	Phase 2	[27]
Ortataxel	DM1EK5D	Solid tumour/cancer	2A00-2F9Z	Phase 2	[28]
Pegsunercept	DMTDANB	Rheumatoid arthritis	FA20	Phase 2	[29]
RDP58	DM4CIKA	Diarrhea	ME05.1	Phase 2	[30]
TNF alpha kinoid	DM3AIF7	Autoimmune diabetes	5A10	Phase 2	[31]
COVA322	DM824EG	Psoriasis vulgaris	EA90	Phase 1/2a	[32]
ART621	DMI17NX	Psoriasis vulgaris	EA90	Phase 1/2	[7]
ABBV-257	DMCZI8L	Rheumatoid arthritis	FA20	Phase 1	[33]
AST-005	DMCN7WI	Psoriasis vulgaris	EA90	Phase 1	[34], [33]
AVX-470	DMAKD0I	Inflammatory bowel disease	DD72	Phase 1	[33]
CYT-609	DMJ83Z7	Solid tumour/cancer	2A00-2F9Z	Phase 1	[35]
INB03	DMCQTLG	Solid tumour/cancer	2A00-2F9Z	Phase 1	[36]
PF-05230905	DM7OC9K	Rheumatoid arthritis	FA20	Phase 1	[37]
PMI-005	DMY9XWB	Osteoarthritis	FA00-FA05	Phase 1	[38]

10 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CDP571	DM4HGMX	Crohn disease	DD70	Discontinued in Phase 3	[39]
Segard	DMIHQZ8	Sepsis	1G40-1G41	Discontinued in Phase 3	[40]
Camobucol	DMS3ECJ	Rheumatoid arthritis	FA20	Discontinued in Phase 2	[41]
CRx-191	DMB9QSJ	Psoriatic disorder	EA90	Discontinued in Phase 2	[42]
AME-527	DMR8XEN	Rheumatoid arthritis	FA20	Discontinued in Phase 1/2	[43]
CYT-007-TNFQb	DMKFIBH	Allergic rhinitis	CA08.0	Discontinued in Phase 1/2	[44]
ALS-00T2-0501	DM2QMKJ	Psoriasis vulgaris	EA90	Discontinued in Phase 1	[45]
FR-133605	DMXWL0N	Arthritis	FA20	Terminated	[48]
MDL-201112	DMMG1K3	Colitis	1A40.Z	Terminated	[49]
TNFQb therapeutic vaccines	DMTNB6G	Crohn disease	DD70	Terminated	[44]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABX-0401	DMKUPW0	Inflammatory bowel disease	DD72	Preclinical	[46]
Celastrol	DMWQIJX	Motor neurone disease	8B60	Preclinical	[47]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-Propanol, Isopropanol	DML5O0H	Discovery agent	N.A.	Investigative	[50]
DOM-0215	DMXJOYH	Discovery agent	N.A.	Investigative	[51]
IK-862	DMJA4UE	Discovery agent	N.A.	Investigative	[52]
PKF-241-466	DM04C9V	Discovery agent	N.A.	Investigative	[53]
PKF-242-484	DMNDLAS	Discovery agent	N.A.	Investigative	[53]
Y-39041	DMC95YB	Discovery agent	N.A.	Investigative	[54]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Osteoarthritis	FA20	Synovial tissue	4.93E-01	0.02	0.09
Rheumatoid arthritis	FA20	Synovial tissue	7.38E-01	-0.07	-0.16
Psoriasis	EA90	Skin	1.24E-17	0.42	1.18
Multiple myeloma	2C82	Bone marrow	1.66E-01	-0.14	-0.65
Neonatal sepsis	1G41	Whole blood	1.82E-05	0.16	0.42
Idiopathic pulmonary fibrosis	CA23	Lung tissue	8.64E-01	-0.06	-0.16
Lateral sclerosis	8A00.0	Cervical spinal cord	8.51E-01	0.05	0.27

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