Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTG043C)

• DTT Name: Tumor necrosis factor receptor type I (TNF-R1)
• Synonyms: p60; p55; Tumor necrosis factor-binding protein 1; Tumor necrosis factor receptor superfamily member 1A; Tumor necrosis factor receptor 1; TNFR1; TNFR-I; TNFAR; TNF-RI; TBPI; CD120a
• Gene Name: TNFRSF1A
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Cytokine receptor
• UniProt ID: TNR1A_HUMAN
• TTD ID: T86552
• Sequence:
  MGLSTVPDLLLPLVLLELLVGIYPSGVIGLVPHLGDREKRDSVCPQGKYIHPQNNSICCT
  KCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVD
  RDTVCGCRKNQYRHYWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLRENECV
  SCSNCKKSLECTKLCLPQIENVKGTEDSGTTVLLPLVIFFGLCLLSLLFIGLMYRYQRWK
  SKLYSIVCGKSTPEKEGELEGTTTKPLAPNPSFSPTPGFTPTLGFSPVPSSTFTSSSTYT
  PGDCPNFAAPRREVAPPYQGADPILATALASDPIPNPLQKWEDSAHKPQSLDTDDPATLY
  AVVENVPPLRWKEFVRRLGLSDHEIDRLELQNGRCLREAQYSMLATWRRRTPRREATLEL
  LGRVLRDMDLLGCLEDIEEALCGPAALPPAPSLLR
• Function: The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase. Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B signaling pathway (hsa04064)
  Sphingolipid signaling pathway (hsa04071)
  Apoptosis (hsa04210)
  Osteoclast differentiation (hsa04380)
  TNF signaling pathway (hsa04668)
  Adipocytokine signaling pathway (hsa04920)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Alzheimer's disease (hsa05010)
  Amyotrophic lateral sclerosis (ALS) (hsa05014)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Influenza A (hsa05164)
  HTLV-I infection (hsa05166)
  Herpes simplex infection (hsa05168)
• Reactome Pathway:
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NFkappaB signaling pathway (R-HSA-5357956)
  TNFR1-mediated ceramide production (R-HSA-5626978)
  TNFs bind their physiological receptors (R-HSA-5669034)
  TNF signaling (R-HSA-75893)
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)

Molecular Interaction Atlas (MIA) of This DTT

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
VB-111	DMX04CA	Malignant glioma	2A00.0	Phase 3	[1]
Drug 2862277	DM8WU3O	Acute lung injury	NB32.3	Phase 2	[2]
AVX-470	DMAKD0I	Inflammatory bowel disease	DD72	Phase 1	[3]
GSK1995057	DMC14KV	Adult respiratory distress syndrome	CB00	Phase 1	[4]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Anti-IFN gamma	DMXI185	Alopecia	ED70	Terminated	[3]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ADS-0101	DMP7IS0	Chronic obstructive pulmonary disease	CA22	Investigative	[2]
ALF-421	DM53KRA	Acute liver failure	DB91	Investigative	[3]
Anti-TNF human mabs	DMYKTF6	Autoimmune diabetes	5A10	Investigative	[3]
NM-2014	DM6RA20	Rheumatoid arthritis	FA20	Investigative	[2]
NM-9405	DMKMBSJ	Rheumatoid arthritis	FA20	Investigative	[2]
Recombinant human TNF receptor	DMLYQWV	Arthritis	FA20	Investigative	[3]
TNFcept	DMAGI7K	Rheumatoid arthritis	FA20	Investigative	[3]
TNFmab	DM4T0ZF	Rheumatoid arthritis	FA20	Investigative	[3]
TNFR1 NAM	DMPTQEG	Multiple sclerosis	8A40	Investigative	[2]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	3.87E-04	1.4	2.55
Glioma	2C82	Brainstem tissue	4.26E-02	-0.48	-3.05
Glioma	2C82	White matter	1.05E-02	-0.11	-0.33
Alopecia	EA90	Skin from scalp	6.73E-02	0.08	0.37
Psoriasis	EA90	Skin	8.10E-01	-0.02	-0.07
Asthma	CA23	Nasal and bronchial airway	1.39E-01	0.11	0.3
Chronic obstructive pulmonary disease	CA23	Lung tissue	1.17E-01	-0.15	-0.3
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	3.28E-01	0.09	0.24
Liver failure	DD91.0	Liver tissue	1.11E-03	-0.71	-1.72

References

• [1] Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors.Clin Cancer Res.2013 Jul 15;19(14):3996-4007.
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1870).
• [3] Secretion of a TNFR:Fc fusion protein following pulmonary administration of pseudotyped adeno-associated virus vectors. J Virol. 2004 Nov;78(22):12355-65.
• [4] Autoantibodies to variable heavy (VH) chain Ig sequences in humans impact the safety and clinical pharmacology of a VH domain antibody antagonist of TNF-alpha receptor 1. J Clin Immunol. 2013 Oct;33(7):1192-203.