TNF

Summary

TNF (tumor necrosis factor, HGNC:11892) is a protein-coding gene on chromosome 6p21.33, encoding Tumor necrosis factor (P01375). Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR.

This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, psoriasis, rheumatoid arthritis ankylosing spondylitis, tuberculosis, autosomal dominant polycystic kidney disease, and cancer. Mutations in this gene affect susceptibility to cerebral malaria, septic shock, and Alzheimer disease. Knockout studies in mice also suggested the neuroprotective function of this cytokine.

Source: NCBI Gene 7124 — RefSeq curated summary.

At a glance

• GWAS associations: 28
• Clinical variants (ClinVar): 26 total — 3 pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes — 12 molecules with ChEMBL bioactivity
• Transcription factor: yes — 56 downstream targets (CollecTRI)
• MANE Select transcript: NM_000594

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11892
Approved symbol	TNF
Name	tumor necrosis factor
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	TNFSF2, DIF, TNF-alpha
Ensembl gene	ENSG00000232810
Ensembl biotype	protein_coding
OMIM	191160
Entrez	7124

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000449264, ENST00000699334

RefSeq mRNA: 1 — MANE Select: NM_000594 NM_000594

CCDS: CCDS4702

Canonical transcript exons

ENST00000376122 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 119 present calls, max score 96.17.

FANTOM5 (CAGE): breadth broad, TPM avg 278.1489 / max 55204.0000, expressed in 807 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66919	271.2923	796
66934	1.3524	131
66933	0.9517	110
66930	0.6799	82
66931	0.6051	79
66943	0.4723	59
66942	0.4628	70
66926	0.4285	66
66929	0.3021	56
66935	0.2690	57

Top tissues by expression

133 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.11	gold quality
bone marrow	UBERON:0002371	86.37	gold quality
leukocyte	CL:0000738	85.79	gold quality
monocyte	CL:0000576	85.61	gold quality
bone marrow cell	CL:0002092	84.38	gold quality
blood	UBERON:0000178	77.44	gold quality
lymph node	UBERON:0000029	77.13	gold quality
spleen	UBERON:0002106	72.08	gold quality
vermiform appendix	UBERON:0001154	71.58	gold quality
duodenum	UBERON:0002114	68.35	gold quality
gall bladder	UBERON:0002110	65.81	gold quality
apex of heart	UBERON:0002098	63.92	gold quality
smooth muscle tissue	UBERON:0001135	62.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	61.57	gold quality
tonsil	UBERON:0002372	61.23	gold quality
placenta	UBERON:0001987	60.86	gold quality
rectum	UBERON:0001052	60.33	gold quality
upper lobe of left lung	UBERON:0008952	59.23	gold quality
metanephros cortex	UBERON:0010533	59.03	gold quality
small intestine	UBERON:0002108	58.30	gold quality
islet of Langerhans	UBERON:0000006	58.08	gold quality
small intestine Peyer’s patch	UBERON:0003454	57.98	gold quality
skin of abdomen	UBERON:0001416	57.84	gold quality
lung	UBERON:0002048	57.39	gold quality
heart left ventricle	UBERON:0002084	57.27	gold quality
omental fat pad	UBERON:0010414	57.27	gold quality
right coronary artery	UBERON:0001625	56.43	gold quality
mucosa of transverse colon	UBERON:0004991	56.20	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	56.13	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-89	yes	731.72
E-CURD-95	yes	487.08
E-CURD-77	yes	293.52
E-MTAB-9467	yes	215.81
E-ANND-3	yes	7.12
E-HCAD-29	no	5009.09

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

56 targets.

Target	Regulation
ALPL	Repression
BACE1	Activation
BMP4	Repression
CCL2	Activation
CCL5	Activation
CD36	Activation
COMT	Repression
CRHBP	Activation
CTSK	Activation
CX3CR1	Activation
CXCL8	Activation
DEFB103A	Activation
DIO1	Repression
DNAH10	Repression
ERBIN	Activation
ESR1	Repression
F3	Activation
GATA2	Repression
HES1	Activation
ICAM1	Activation
IDE	Activation
IL1B	Activation
IL33	Activation
IL6	Activation
JAG2	Activation
KDR	Repression
LGALS9	Activation
LPL	Unknown
MC1R	Repression
MIF	Activation

Upstream regulators (CollecTRI, top): AEBP1, AHR, ANXA1, AP1, APEX1, APP, AR, ARNT, ATF1, ATF2, ATF3, ATF4, ATF7, BCL3, BRD4, CCL3, CEBPA, CEBPB, CEBPD, CEBPE, CEBPG, CREB1, CREM, CTCF, DIDO1, DLL4, DLX4, DNMT1, E2F1, E2F3, EBF1, EGR1, EGR2, EGR3, EGR4, ELK1, EP300, ESR1, ESR2, ETS1

miRNA regulators (miRDB)

59 targeting TNF, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4261	99.59	70.30	3415

Literature-anchored findings (GeneRIF, showing 40)

• A high in vivo and in vitro production of TNF-alpha found in carriers of the common Caucasoid haplotype HLA-B8,DR3 is associated with multiple autoimmune diseases and immune response dysregulation in healthy subjects. (PMID:11423177)
• Elevated tumour necrosis factor-alpha levels may play a role in the development of necrotizing enterocolitis. The A(-308) and A(-238) variants of the promoter region of the TNF-alpha gene are reportedly associated with altered TNF-alpha production. (PMID:11697432)
• -A significantly reduced PGN-elicited tumor necrosis factor alpha (TNF-alpha) secretion by U937 cells and rat alveolar macrophages. (PMID:11724772)
• Anti-TNF therapy for rheumatoid arthritis and other inflammatory diseases (PMID:11725485)
• affects susceptibility to acute rejection after cardiac transplantation (PMID:11744409)
• Interleukin-6, tumor necrosis factor alpha and interferon gamma serum levels in patients with anorexia nervosa. (PMID:11774563)
• Postburn plasma TNF alpha level increased in all patients, especially obvious in those with sepsis. (PMID:11774822)
• PAI-1 gene activation by TNF-alpha apparently is yet to be defined for the location of the response element and/or the signaling pathway, while TGF-beta is the most important cytokine for PAI-1 transcriptional activation through its 5’ proximal promoter. (PMID:11776328)
• effect on cell proliferation and apoptosis in conjunction with interferon-gamma (PMID:11781187)
• CD40 ligation induces macrophage IL-10 and TNF-alpha production: differential use of the PI3K and p42/44 MAPK-pathways. (PMID:11792123)
• Damage of the ehdothelial cells of placental blood vessels is associated with the abnormal increase in the maternal blood TNFalpha. (PMID:11798770)
• role of PTEN in blocking induction of NF-kapp B-dependent transcription by inhibiting the transactivation potential of the p65 subunt (PMID:11799112)
• TNF-alpha potentiates adhesion of C5a-stimulated eosinophils to human bronchial epithelial cells (HBEC) by a mechanism in which eosinophil contact with HBEC is essential for priming. (PMID:11801679)
• The phagocytosis of platelets opsonised by anti-beta2GPI antibodies determined the release of TNF-alpha and IL-1beta by dendritic cells and macrophages. (PMID:11816715)
• The role of TNF/TNFR in organ-specific and systemic autoimmunity is reviewed: implications for the design of optimized ‘anti-TNF’ therapies. (PMID:11826759)
• Critical role of tumor necrosis factor-alpha and NF-kappa B in interferon-gamma -induced CD40 expression in microglia/macrophages. (PMID:11830590)
• Transient exposure of human bronchial epithelial cells to TNFA leads to persistent increased expression of ICAM-1. (PMID:11831440)
• Incubation of endothelial cells with conditioned media derived from stimulated macrophages modulates ICAM1 mRNA expression. Results suggest TNF-alpha and activation of the NF-kB pathway are involved. (PMID:11831864)
• The A1 allele of TNF-alpha associates with rheumatoid arthritis.Genotypes A1A2 of TNF-alpha is associated with more severe disease. (PMID:11838837)
• Breast cancer is not associated with SNPs in the TNFA promoters; TNFB*A allele induces some function(s) leading to the inhibition of tumorigenesis in breast cancer (PMID:11841482)
• Genetic variation in TNFalpha production is unlikely to play a major role in risk of cutaneous malignant melanoma. (PMID:11841484)
• association of TNF alleles with HLA-DR, -DQ and -B alleles in 216 healthy individuals from the north of England (PMID:11841486)
• Genetic polymorphisms in the TNF-alpha gene at positions -376, -308, -238 and +489 could not be identified as susceptibility or severity factors in periodontitis (PMID:11846846)
• TNF-deficient mice are protected from experimental allergic encephalomyelitis. (PMID:11847479)
• TNF-alpha–accelerated apoptosis abrogates ANCA-mediated neutrophil respiratory burst by a caspase-dependent mechanism. (PMID:11849390)
• Carriage of ILbeta2 and IL1RN*2, together with non-carriage of TNF2is associated with increased susceptibility, but not with a prognosis of IgAN. (PMID:11849463)
• Polymorphisms in or near tumour necrosis factor (TNF)-gene do not determine levels of endotoxin-induced TNF production. (PMID:11857057)
• In dengue shock syndrome pts, TNF-alpha was significantly associated with D-dimer, an activation marker of fibrinolysis (p < 0.003), but not with activation markers of coagulation. TNF-alpha is involved in the onset and regulation of hemostasis. (PMID:11858187)
• TNF alpha-mediated effect causes or contributes to defective bone marrow progenitor cell reserve and function and defective stromal cell function in rheumatoid arthritis. (PMID:11861275)
• Ubiquitin/proteasome-dependent degradation of D-type cyclins is linked to tumor necrosis factor-induced cell cycle arrest. (PMID:11864973)
• in semen of normal/infertile men (PMID:11868623)
• no significant differences in basal TNFalpha levels were found between the growth hormone deficient, idiopathic short stature children and healthy controls (PMID:11874184)
• ). TNF-alpha promoter polymorphisms are associated with severe, but not less severe, silicosis in this population. (PMID:11874815)
• Stimulation of IRF-7 gene expression by tumor necrosis factor alpha: requirement for NFkappa B transcription factor and gene accessibility (PMID:11877397)
• role in inducing interleukin-6 and interleukin-8 secretion in bronial epithelia cells (PMID:11884401)
• the pathophysiological role of the tumor necrosis factor (TNF) system in insulin resistance in patients with gestational diabetes (GDM) and during the course of normal pregnancy (PMID:11891016)
• promoter polymorphism in NIDDM in japan; relationahip to insulin sensitivity and abdominal fat (PMID:11891022)
• Promoter polymorphism TNFalpha-308*2 increases risk of asthma. (PMID:11896460)
• Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn’s disease, respectively. (PMID:11904678)
• Proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. (PMID:11907116)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tnf	ENSMUSG00000024401
rattus_norvegicus	Tnf	ENSRNOG00000070745

Paralogs (8): CD40LG (ENSG00000102245), FASLG (ENSG00000117560), TNFSF11 (ENSG00000120659), TNFSF10 (ENSG00000121858), TNFSF14 (ENSG00000125735), TNFSF15 (ENSG00000181634), LTA (ENSG00000226979), LTB (ENSG00000227507)

Protein

Protein identifiers

Tumor necrosis factor — P01375 (reviewed: P01375)

Alternative names: Cachectin, TNF-alpha, Tumor necrosis factor ligand superfamily member 2

All UniProt accessions (3): P01375, A0A8V8TNL2, Q5STB3

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. 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. Up-regulates 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. Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6. Promotes osteoclastogenesis and therefore mediates bone resorption. The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.

Subunit / interactions. Homotrimer. Interacts with SPPL2B.

Subcellular location. Cell membrane Membrane Secreted Secreted Secreted.

Post-translational modifications. The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into the extracellular space. The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1. O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid. The soluble form is demyristoylated at Lys-19 and Lys-20 by SIRT6, promoting its secretion.

Disease relevance. Psoriatic arthritis (PSORAS) [MIM:607507] An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoid like pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). Disease susceptibility is associated with variants affecting the gene represented in this entry. Immunodeficiency 127 (IMD127) [MIM:620977] An autosomal recessive immunologic disorder characterized by increased susceptibility to pulmonary infection with Mycobacterium tuberculosis. Affected individuals develop recurrent pulmonary tuberculosis, but have no adverse reaction to live BCG vaccination. The disease may be caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424]. Genetic variations in TNF are involved in susceptibility to malaria [MIM:611162].

Similarity. Belongs to the tumor necrosis factor family.

RefSeq proteins (1): NP_000585* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002959	TNF_alpha	Family
IPR006052	TNF_dom	Domain
IPR006053	TNF	Family
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR021184	TNF_CS	Conserved_site

Pfam: PF00229

UniProt features (56 total): strand 18, mutagenesis site 8, chain 6, site 5, sequence conflict 3, helix 3, lipid moiety-binding region 2, sequence variant 2, turn 2, topological domain 2, modified residue 1, glycosylation site 1, disulfide bond 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

52 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9OJO	X-RAY DIFFRACTION	1.36
5UUI	X-RAY DIFFRACTION	1.4
4Y6O	X-RAY DIFFRACTION	1.6
2E7A	X-RAY DIFFRACTION	1.8
4TSV	X-RAY DIFFRACTION	1.8
9OJS	X-RAY DIFFRACTION	1.85
5M2J	X-RAY DIFFRACTION	1.9
9BN7	X-RAY DIFFRACTION	1.92
2AZ5	X-RAY DIFFRACTION	2.1
3L9J	X-RAY DIFFRACTION	2.1
7JRA	X-RAY DIFFRACTION	2.1
5M2I	X-RAY DIFFRACTION	2.15
7KP9	X-RAY DIFFRACTION	2.15
9OJY	X-RAY DIFFRACTION	2.16
1A8M	X-RAY DIFFRACTION	2.3
5M2M	X-RAY DIFFRACTION	2.3
7KPA	X-RAY DIFFRACTION	2.3
21TW	ELECTRON MICROSCOPY	2.43
2ZJC	X-RAY DIFFRACTION	2.5
5TSW	X-RAY DIFFRACTION	2.5
6OOY	X-RAY DIFFRACTION	2.5
7TA3	X-RAY DIFFRACTION	2.5
6OP0	X-RAY DIFFRACTION	2.55
8ZUI	ELECTRON MICROSCOPY	2.56
8Z8M	X-RAY DIFFRACTION	2.59
1TNF	X-RAY DIFFRACTION	2.6
4G3Y	X-RAY DIFFRACTION	2.6
6RMJ	X-RAY DIFFRACTION	2.65
7TA6	X-RAY DIFFRACTION	2.67
5YOY	X-RAY DIFFRACTION	2.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01375-F1	84.72	0.63

Antibody-complex structures (SAbDab): 9 — 3WD5, 4G3Y, 5M2I, 5M2J, 5M2M, 5WUX, 5YOY, 7KPB, 8Z8M

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (5): 35–36 (cleavage; by sppl2a or sppl2b); 39–40 (cleavage; by sppl2a or sppl2b); 49–50 (cleavage; by sppl2a or sppl2b); 51–52 (cleavage; by sppl2a or sppl2b); 76–77 (cleavage; by adam17)

Post-translational modifications (3): 2, 19, 20

Disulfide bonds (1): 145–177

Glycosylation sites (1): 80

Mutagenesis-validated functional residues (8):

Position	Phenotype
19–20	abolished myristoylation.
105	low activity.
108	biologically inactive.
112	biologically inactive.
160	biologically inactive.
162	biologically inactive.
167	biologically inactive.
222	biologically inactive.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway
R-HSA-5626978	TNFR1-mediated ceramide production
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway
R-HSA-6783783	Interleukin-10 signaling
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-75893	TNF signaling
R-HSA-9942503	Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)

MSigDB gene sets: 1363 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CIRCADIAN_RHYTHM, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, PID_HDAC_CLASSI_PATHWAY, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_HEPATOCYTE_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, BIOCARTA_RELA_PATHWAY, MODULE_52, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_RESPONSE_TO_ETHANOL

GO Biological Process (204): negative regulation of transcription by RNA polymerase II (GO:0000122), protein polyubiquitination (GO:0000209), response to hypoxia (GO:0001666), microglial cell activation (GO:0001774), positive regulation of cytokine production (GO:0001819), positive regulation of protein phosphorylation (GO:0001934), negative regulation of endothelial cell proliferation (GO:0001937), response to amphetamine (GO:0001975), negative regulation of L-glutamate import across plasma membrane (GO:0002037), macrophage activation involved in immune response (GO:0002281), chronic inflammatory response to antigenic stimulus (GO:0002439), positive regulation of immunoglobulin production (GO:0002639), negative regulation of cytokine production involved in immune response (GO:0002719), positive regulation of chronic inflammatory response to antigenic stimulus (GO:0002876), positive regulation of humoral immune response mediated by circulating immunoglobulin (GO:0002925), skeletal muscle contraction (GO:0003009), negative regulation of systemic arterial blood pressure (GO:0003085), glucose metabolic process (GO:0006006), inflammatory response (GO:0006954), immune response (GO:0006955), humoral immune response (GO:0006959), canonical NF-kappaB signal transduction (GO:0007249), JNK cascade (GO:0007254), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), circadian rhythm (GO:0007623), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), response to xenobiotic stimulus (GO:0009410), response to virus (GO:0009615), response to salt stress (GO:0009651), response to fructose (GO:0009750), negative regulation of heart rate (GO:0010459), vascular endothelial growth factor production (GO:0010573), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), positive regulation of macrophage derived foam cell differentiation (GO:0010744), negative regulation of lipid storage (GO:0010888), response to activity (GO:0014823), calcium-mediated signaling (GO:0019722), extracellular matrix organization (GO:0030198)

GO Molecular Function (9): transcription cis-regulatory region binding (GO:0000976), protease binding (GO:0002020), cytokine activity (GO:0005125), tumor necrosis factor receptor binding (GO:0005164), death receptor agonist activity (GO:0038177), identical protein binding (GO:0042802), receptor ligand activity (GO:0048018), histone H3K9ac reader activity (GO:0140072), protein binding (GO:0005515)

GO Cellular Component (10): phagocytic cup (GO:0001891), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), neuronal cell body (GO:0043025), membrane raft (GO:0045121), recycling endosome (GO:0055037), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
TNF signaling	4
Signaling by Interleukins	2
Adipogenesis	1
Cytokine Signaling in Immune system	1
Death Receptor Signaling	1
Differentiation of T cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
macrophage activation	2
receptor ligand activity	2
plasma membrane	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
protein ubiquitination	1
response to stress	1
response to decreased oxygen levels	1
leukocyte activation involved in inflammatory response	1
glial cell activation	1
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
negative regulation of epithelial cell proliferation	1
response to amine	1
regulation of L-glutamate import across plasma membrane	1
negative regulation of organic acid transport	1
negative regulation of transmembrane transport	1
negative regulation of amino acid transport	1
L-glutamate import across plasma membrane	1
myeloid cell activation involved in immune response	1
leukocyte activation involved in immune response	1
immune response	1
inflammatory response to antigenic stimulus	1
chronic inflammatory response	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
negative regulation of cytokine production	1
cytokine production involved in immune response	1
negative regulation of production of molecular mediator of immune response	1

Protein interactions and networks

STRING

10273 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNF	TNFRSF1A	P19438	999
TNF	TNFRSF1B	P20333	998
TNF	TNFRSF10A	O00220	997
TNF	TNFRSF10B	O14763	997
TNF	FAS	P25445	997
TNF	TRADD	Q15628	996
TNF	IL1R1	P14778	996
TNF	NFKB1	P19838	995
TNF	TRAF6	Q9Y4K3	995
TNF	IL1B	P01584	993
TNF	IFNG	P01579	990
TNF	IL6	P05231	989
TNF	TNFRSF25	P78507	987
TNF	FASLG	P48023	984
TNF	CD40	P25942	984
TNF	IL10	P22301	984

IntAct

212 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
TNF	TNFRSF1A	psi-mi:“MI:0914”(association)	0.960
TNF	TNFRSF1A	psi-mi:“MI:0915”(physical association)	0.960
TNFRSF1A	TNF	psi-mi:“MI:0407”(direct interaction)	0.960
TNFRSF1A	TNF	psi-mi:“MI:0915”(physical association)	0.960
TNF	TNFRSF1A	psi-mi:“MI:0407”(direct interaction)	0.960
TNFRSF1A	TNF	psi-mi:“MI:2364”(proximity)	0.960
TNF	TRAF2	psi-mi:“MI:0914”(association)	0.840
TRADD	TNF	psi-mi:“MI:0914”(association)	0.790
TNF	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.790
TNF	TNFRSF1B	psi-mi:“MI:0407”(direct interaction)	0.790
TNF	TNF	psi-mi:“MI:0407”(direct interaction)	0.730

BioGRID (631): TNF (Affinity Capture-RNA), TNF (Protein-RNA), TNFRSF1A (Reconstituted Complex), TNFRSF1B (Reconstituted Complex), TNF (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), INTS5 (Affinity Capture-MS), CPD (Affinity Capture-MS), RHEB (Affinity Capture-MS), ABCB6 (Affinity Capture-MS), NCR3LG1 (Affinity Capture-MS), GK (Affinity Capture-MS), NCLN (Affinity Capture-MS), DDX19B (Affinity Capture-MS), GLS (Affinity Capture-MS)

ESM2 similar proteins: O35734, O77510, O77764, O95150, O97605, O97626, P01375, P04924, P06804, P13296, P16599, P19101, P23383, P23563, P27548, P29553, P29965, P33620, P36939, P36940, P41047, P48094, P51435, P51742, P51743, P51749, P59684, P59693, P59694, P59695, P63305, P79337, P79374, Q06599, Q19LH4, Q1G1A2, Q1WM27, Q2MH05, Q539C2, Q5UBV8

Diamond homologs: O35734, O77510, O77764, P01374, P01375, P04924, P06804, P09225, P10154, P13296, P16599, P19101, P23383, P23563, P26445, P29553, P33620, P36939, P48023, P48094, P51435, P51742, P51743, P59684, P59693, P59694, P59695, P61125, P63306, P63307, P63308, P79337, P79374, Q06332, Q06599, Q06600, Q19LH4, Q1G1A2, Q1WM27, Q2MH05

SIGNOR signaling

100 interactions.

A	Effect	B	Mechanism
TNF	up-regulates	AKT1
TNF	up-regulates	AKT2
TNF	down-regulates	IRS1
TNF	“up-regulates activity”	TNFRSF1A	binding
STAG2	up-regulates	TNF
TNF	“up-regulates activity”	MAPK14
TNF	down-regulates	Adipogenesis
doramapimod	down-regulates	TNF	“chemical inhibition”
SIRT6	up-regulates	TNF	deacetylation
TNF	up-regulates	AKT
FCGR3A	“up-regulates quantity by expression”	TNF
HBB	“up-regulates quantity by expression”	TNF	“transcriptional regulation”
HBA1	“up-regulates quantity by expression”	TNF	“transcriptional regulation”
TNF	“down-regulates quantity by repression”	LPL	“transcriptional regulation”
TNF	“down-regulates quantity by repression”	SCNN1A	“transcriptional regulation”
“UVB radiation”	up-regulates	TNF
IL1A	“up-regulates quantity by expression”	TNF	“transcriptional regulation”
TNF	“up-regulates activity”	GCH1
MC1R	“down-regulates quantity by repression”	TNF	“transcriptional regulation”
TNF	“down-regulates activity”	MC1R	“transcriptional regulation”
TNF	“up-regulates quantity by expression”	NOD2	“transcriptional regulation”
TNF	“up-regulates quantity by expression”	RIPK2	“transcriptional regulation”
“A9/b1 integrin”	“up-regulates quantity by expression”	TNF
TNF	“up-regulates quantity by expression”	HES1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 91 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TNF signaling	8	60.4×	7e-11
TNFR1-induced NF-kappa-B signaling pathway	10	60.0×	2e-13
TNFR1-induced proapoptotic signaling	7	54.9×	4e-09
TRAF6 mediated NF-kB activation	6	48.9×	2e-07
Regulation of TNFR1 signaling	11	44.0×	2e-13
NOD1/2 Signaling Pathway	5	28.3×	5e-05
TAK1-dependent IKK and NF-kappa-B activation	5	26.8×	6e-05
Ovarian tumor domain proteases	5	24.9×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
canonical NF-kappaB signal transduction	9	49.2×	6e-11
tumor necrosis factor-mediated signaling pathway	7	34.5×	2e-07
negative regulation of canonical NF-kappaB signal transduction	11	28.2×	6e-11
obsolete positive regulation of NF-kappaB transcription factor activity	6	18.4×	1e-04
positive regulation of canonical NF-kappaB signal transduction	12	13.0×	3e-08
cellular response to tumor necrosis factor	5	12.2×	3e-03
T cell receptor signaling pathway	5	11.3×	4e-03
positive regulation of inflammatory response	5	10.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

26 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	10
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
12385	L29S	Pathogenic
12386	NM_000594.4(TNF):c.322C>T (p.Arg108Trp)	Pathogenic
3362893	TNF, 20-BP INS, NT190	Pathogenic

SpliceAI

205 predictions. Top by Δscore:

Variant	Effect	Δscore
6:31575924:AGAG:A	donor_gain	1.0000
6:31575924:AGAGG:A	donor_loss	1.0000
6:31575925:GAG:G	donor_gain	1.0000
6:31575925:GAGG:G	donor_gain	1.0000
6:31575925:GAGGT:G	donor_loss	1.0000
6:31575926:AG:A	donor_gain	1.0000
6:31575927:GG:G	donor_gain	1.0000
6:31575927:GGTG:G	donor_loss	1.0000
6:31575928:G:GG	donor_gain	1.0000
6:31576532:A:AG	acceptor_gain	1.0000
6:31576533:G:GG	acceptor_gain	1.0000
6:31576576:GTCA:G	donor_gain	1.0000
6:31576580:G:GG	donor_gain	1.0000
6:31576763:TCAG:T	acceptor_loss	1.0000
6:31576764:CAGG:C	acceptor_loss	1.0000
6:31576765:A:AG	acceptor_gain	1.0000
6:31576765:A:AT	acceptor_loss	1.0000
6:31576765:AG:A	acceptor_gain	1.0000
6:31576766:G:GT	acceptor_gain	1.0000
6:31576766:GG:G	acceptor_gain	1.0000
6:31576766:GGAT:G	acceptor_gain	1.0000
6:31576766:GGATC:G	acceptor_gain	1.0000
6:31576810:TGTAG:T	donor_loss	1.0000
6:31576816:T:A	donor_loss	1.0000
6:31577114:A:AG	acceptor_gain	1.0000
6:31577115:G:GA	acceptor_gain	1.0000
6:31577115:GC:G	acceptor_gain	1.0000
6:31577115:GCA:G	acceptor_gain	1.0000
6:31577115:GCAA:G	acceptor_gain	1.0000
6:31577115:GCAAA:G	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000202700 (6:31574929 G>A), RS1000808024 (6:31576897 G>A,C), RS1003548402 (6:31578311 GA>G), RS1003854190 (6:31576162 T>C), RS1004416271 (6:31574355 G>A), RS1006268320 (6:31577847 A>G), RS1006944565 (6:31577947 A>G), RS1007382983 (6:31578466 T>C), RS1007655911 (6:31576900 A>G), RS1008158430 (6:31573972 G>A), RS1008522396 (6:31574230 G>A), RS1010428752 (6:31578786 A>G), RS1010734656 (6:31576441 T>C,G), RS1011194458 (6:31573866 C>T), RS1011879047 (6:31576120 G>T)

Disease associations

OMIM: gene MIM:191160 | disease phenotypes: MIM:157300, MIM:600807, MIM:607507, MIM:620977

GenCC curated gene-disease

Mondo (5): migraine with or without aura, susceptibility to, 1 (MONDO:0008000), endometriosis (MONDO:0005133), inherited susceptibility to asthma (MONDO:0010940), psoriatic arthritis, susceptibility to (MONDO:0100232), immunodeficiency 127 (MONDO:0975832)

Orphanet (0):

HPO phenotypes

17 total (18 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000613	Photophobia
HP:0001426	Non-Mendelian inheritance
HP:0002013	Vomiting
HP:0002018	Nausea
HP:0002077	Migraine with aura
HP:0002083	Migraine without aura
HP:0002099	Asthma
HP:0002183	Phonophobia
HP:0002202	Pleural effusion
HP:0010516	Thymus hyperplasia
HP:0011462	Young adult onset
HP:0031273	Shock
HP:0032262	Pulmonary tuberculosis
HP:0032933	Airway hyperresponsiveness
HP:4000007	Bronchoconstriction
HP:0030127	Endometriosis

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000308_1	AIDS progression	3.000000e-19
GCST000738_5	Neonatal lupus	5.000000e-10
GCST000879_24	Crohn’s disease	4.000000e-11
GCST002211_10	Psychosis (atypical)	4.000000e-06
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_27	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_3	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST004833_9	Cervical cancer	6.000000e-09
GCST007269_246	Pulse pressure	8.000000e-19
GCST008916_111	Asthma	2.000000e-14
GCST008916_114	Asthma	1.000000e-09
GCST008916_30	Asthma	1.000000e-09
GCST008917_2	Asthma (childhood onset)	4.000000e-07
GCST008921_1	Asthma and major depressive disorder	2.000000e-16
GCST010725_43	Malaria	5.000000e-07
GCST010725_62	Malaria	3.000000e-06
GCST011773_10	Type 1 diabetes (age at diagnosis)	3.000000e-07
GCST012230_370	Waist-to-hip ratio adjusted for BMI	3.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0004918	age at diagnosis
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D004715	Endometriosis	C12.050.351.500.163; C12.100.250.163

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1825 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

12 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 291,559 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL131	PREDNISOLONE	4	140,604
CHEMBL43452	POMALIDOMIDE	4	13,354
CHEMBL628	PENTOXIFYLLINE	4	26,061
CHEMBL704	MESALAMINE	4	52,574
CHEMBL848	LENALIDOMIDE	4	5,256
CHEMBL279785	MARIMASTAT	3	29,447
CHEMBL3989927	IBERDOMIDE	3	1,300
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL3989934	AVADOMIDE	2	1,506
CHEMBL4207852	MIZACORAT	2	106
CHEMBL4574601	LINPERLISIB	2	150
CHEMBL63	ROLIPRAM	2	19,520

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

18 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1799724	Efficacy	4	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Crohn Disease;Psoriasis;Rheumatoid arthritis;Spondylitis;Ankylosing
rs1799964	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Spondylitis;Ankylosing
rs1799964	Toxicity	3	stavudine	HIV infectious disease
rs1800629	Efficacy	3	diclofenac	Migraine without Aura
rs1800629	Efficacy	3	ibuprofen	Migraine without Aura
rs1800629	Efficacy	3	indomethacin	Migraine without Aura
rs1800629	Efficacy	3	ketorolac	Migraine without Aura
rs1800629	Efficacy	3	naproxen	Migraine without Aura
rs1800629	Toxicity	3	carbamazepine	Hypersensitivity
rs1800629	Efficacy	2B	etanercept	Arthritis;Psoriatic;Crohn Disease;Inflammation;Psoriasis;Rheumatoid arthritis;Spondylitis;Ankylosing
rs1800629	Other	3	atorvastatin	Acute coronary syndrome
rs1800629	Efficacy	3	cyclosporine;mycophenolate mofetil	Kidney Transplantation
rs1800629	Toxicity	3	ethambutol;isoniazid;pyrazinamide;rifampin	Toxic liver disease;Tuberculosis
rs1800629	Toxicity	3	carboplatin;gemcitabine	Non-Small Cell Lung Carcinoma;Thrombocytopenia
rs1800629	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs1800629	Toxicity	3	sorafenib	Hand-foot syndrome;Hepatocellular Carcinoma
rs1800629	Efficacy	3	aspirin	Migraine without Aura
rs361525	Efficacy	3	infliximab

PharmGKB variants

19 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs361525	TNF	3	2.25	1	infliximab
rs1799724	LTA, TNF	4	-0.88	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs1799964	LTA, TNF	3	2.50	2	Tumor necrosis factor alpha (TNF-alpha) inhibitors;stavudine
rs1800610	TNF		0.00	0
rs1800629	LST1, LTA, TNF	2B	14.62	14	etanercept;carbamazepine;ethambutol;isoniazid;pyrazinamide;rifampin;sorafenib;Tumor necrosis factor alpha (TNF-alpha) inhibitors;cyclosporine;mycophenolate mofetil;atorvastatin;carboplatin;gemcitabine;aspirin;diclofenac
rs1800630	LTA, TNF		0.00	0
rs1800750	TNF		0.00	0
rs2736195	TNF		0.00	0
rs3093548	TNF		0.00	0
rs3093726	LST1, LTA, LTB, TNF	3	0.00	1	abacavir
rs4248158	LTA, TNF		0.00	0
rs4248159	LTA, TNF		0.00	0
rs4248160	TNF		0.00	0
rs4248163	TNF		0.00	0
rs4647198	LTA, TNF		0.00	0
rs4987086	LTA, TNF		0.00	0
rs55634887	TNF		0.00	0
rs55994001	TNF		0.00	0
rs3093662	TNF		0.00	0

Binding affinities (BindingDB)

1745 measured of 2268 human assays (2320 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
7-[(E)-but-2-enyl]-3-methyl-8-(3-phenylpropylsulfanyl)purine-2,6-dione	EC50	0.00868 nM
(5R)-5-[(4-fluoro-5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-(4-fluoro-3-oxo-1,2-dihydroindazol-6-yl)ethynyl]imidazolidine-2,4-dione	KI	0.03 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[5-(1H-pyrazol-4-yl)-3-pyridinyl]ethynyl]imidazolidine-2,4-dione	KI	0.03 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-(4-fluoro-3-oxo-1,2-dihydroindazol-6-yl)ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.0521 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[3-hydroxy-6-(1-methylpyrazol-4-yl)-2-pyridinyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.0524 nM	US-8541572: Compounds for the treatment of inflammatory disorders
US8541572, 970	KI	0.0556 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[5-(1H-pyrazol-5-yl)-3-pyridinyl]ethynyl]imidazolidine-2,4-dione	KI	0.06 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[3-fluoro-4-[3-hydroxy-6-(1-methylpyrazol-4-yl)-2-pyridinyl]phenyl]ethynyl]-5-[(4-fluoro-5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.0627 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[(4-cycloheptylpiperazin-1-yl)-nitrosomethyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.063 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-(3-hydroxy-6-pyridin-3-yl-2-pyridinyl)phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.0651 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[(4-cyclopropylpiperazin-1-yl)-nitrosomethyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.072 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-(3-hydroxy-2-pyridinyl)phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.074 nM	US-8541572: Compounds for the treatment of inflammatory disorders
[2-[4-[2-[(4R)-4-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]phenyl]-3-pyridinyl] 2,2-dimethylpropanoate	KI	0.0762 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[3-fluoro-4-(3-hydroxy-6-pyridin-3-yl-2-pyridinyl)phenyl]ethynyl]-5-[(4-fluoro-5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.077 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(4-fluoro-5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-(3-hydroxy-6-pyridin-3-yl-2-pyridinyl)phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.0781 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(4-fluoro-5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-[3-hydroxy-6-(4-oxopiperidin-1-yl)-2-pyridinyl]phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.0826 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-[(4-methylpiperazin-1-yl)-nitrosomethyl]phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.083 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[(Z)-C-(4-butylpiperazin-1-yl)-N-hydroxycarbonimidoyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.093 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[6-(4-ethylpiperazin-1-yl)-3-hydroxy-2-pyridinyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.093 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(4-fluoro-5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-[3-hydroxy-6-(1-methylpyrazol-4-yl)-2-pyridinyl]phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.0973 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[6-(4-ethylpiperazin-1-yl)-3-hydroxy-2-pyridinyl]-3-fluorophenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.0988 nM	US-8541572: Compounds for the treatment of inflammatory disorders
5-[4-[2-[(4R)-4-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]-3-methylphenyl]-5-methylimidazolidine-2,4-dione	KI	0.1 nM	US-8541572: Compounds for the treatment of inflammatory disorders
2-[2-[(4R)-4-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]benzaldehyde	KI	0.11 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[(4-cyclohexylpiperazin-1-yl)-nitrosomethyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.11 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(4-fluoro-5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-(2-pyridin-3-ylethynyl)imidazolidine-2,4-dione	KI	0.11 nM	US-8541572: Compounds for the treatment of inflammatory disorders
[2-[4-[2-[(4R)-4-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]phenyl]-6-(1-methylpyrazol-4-yl)-3-pyridinyl] propanoate	KI	0.115 nM	US-8541572: Compounds for the treatment of inflammatory disorders
N-cyclopropyl-1-[4-[2-[(4R)-4-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]phenyl]-5-oxopyrrolidine-2-carboxamide	KI	0.12 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-[nitroso(piperidin-1-yl)methyl]phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.12 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[5-[(4-methylpiperazin-1-yl)-nitrosomethyl]thiophen-2-yl]ethynyl]imidazolidine-2,4-dione	KI	0.12 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[2-(1H-pyrazol-4-yl)-3-pyridinyl]ethynyl]imidazolidine-2,4-dione	KI	0.12 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[2-(4-ethylpiperazine-1-carbonyl)-5-oxopyrrolidin-1-yl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.13 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-[morpholin-4-yl(nitroso)methyl]phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.13 nM	US-8541572: Compounds for the treatment of inflammatory disorders
3-[2-[(4R)-4-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]-4-methylbenzamide	KI	0.15 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[5-(2-amino-1,3-thiazol-4-yl)-3-pyridinyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.15 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-[nitroso-(4-phenylpiperazin-1-yl)methyl]phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.15 nM	US-8541572: Compounds for the treatment of inflammatory disorders
5-(aminomethyl)-5-[4-[2-[(4R)-4-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]phenyl]imidazolidine-2,4-dione	KI	0.16 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-(2,2,2-trifluoro-1,1-dihydroxyethyl)phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.16 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[(4-ethylpiperazin-1-yl)-nitrosomethyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.16 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-[nitroso(thiomorpholin-4-yl)methyl]phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.16 nM	US-8541572: Compounds for the treatment of inflammatory disorders
N-[4-[2-[(4R)-4-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]phenyl]-1-methylpiperidine-4-carboxamide	KI	0.17 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[3-(4-ethylpiperazin-1-yl)-1H-indazol-6-yl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.17 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-(4-cyclobutyl-2,5-dioxoimidazolidin-4-yl)phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.17 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-[nitroso-(4-oxopiperidin-1-yl)methyl]phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.17 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[[(2S)-4-ethyl-2-methylpiperazin-1-yl]-nitrosomethyl]-3-fluorophenyl]ethynyl]-5-[(4-fluoro-5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.18 nM	US-8541572: Compounds for the treatment of inflammatory disorders
N-[5-[2-[(4R)-4-[(4-fluoro-5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]-3-pyridinyl]-1-methylpiperidine-4-carboxamide	KI	0.18 nM	US-8541572: Compounds for the treatment of inflammatory disorders
5-[5-[2-[(4R)-4-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]-1-benzofuran-2-yl]-5-methylimidazolidine-2,4-dione	KI	0.18 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[3-[morpholin-4-yl(nitroso)methyl]phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.18 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[6-[(4-ethylpiperazin-1-yl)-nitrosomethyl]-3-pyridinyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.18 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[2-[4-[[2-(2-morpholin-4-ylethylamino)-3,4-dioxocyclobuten-1-yl]amino]phenyl]ethynyl]imidazolidine-2,4-dione	KI	0.19 nM	US-8541572: Compounds for the treatment of inflammatory disorders
(5R)-5-[2-[4-[(2-amino-3,4-dioxocyclobuten-1-yl)amino]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	KI	0.19 nM	US-8541572: Compounds for the treatment of inflammatory disorders

ChEMBL bioactivities

2128 potent at pChembl≥5 of 2362 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.52	Ki	0.03	nM	CHEMBL3640299
10.52	Ki	0.03	nM	CHEMBL3642435
10.28	Ki	0.0521	nM	CHEMBL3640298
10.28	Ki	0.0524	nM	CHEMBL3640339
10.25	Ki	0.0556	nM	CHEMBL3640336
10.22	Ki	0.06	nM	CHEMBL3642459
10.20	Ki	0.0627	nM	CHEMBL3640352
10.20	Ki	0.063	nM	CHEMBL3642501
10.19	Ki	0.0651	nM	CHEMBL3640337
10.14	Ki	0.072	nM	CHEMBL3642496
10.13	Ki	0.074	nM	CHEMBL1288000
10.12	Ki	0.0762	nM	CHEMBL3640370
10.11	Ki	0.0781	nM	CHEMBL3640366
10.11	Ki	0.077	nM	CHEMBL3640367
10.08	Ki	0.0826	nM	CHEMBL3640368
10.08	Ki	0.083	nM	CHEMBL3642511
10.03	Ki	0.093	nM	CHEMBL3642499
10.03	Ki	0.093	nM	CHEMBL3642508
10.01	Ki	0.0988	nM	CHEMBL1288726
10.01	Ki	0.0973	nM	CHEMBL3640351
10.00	Ki	0.1	nM	CHEMBL3642518
9.96	Ki	0.11	nM	CHEMBL3640417
9.96	Ki	0.11	nM	CHEMBL3642500
9.96	Ki	0.11	nM	CHEMBL3642528
9.94	Ki	0.115	nM	CHEMBL3640353
9.92	Ki	0.12	nM	CHEMBL3640402
9.92	Ki	0.12	nM	CHEMBL3642513
9.92	Ki	0.12	nM	CHEMBL3642514
9.92	Ki	0.12	nM	CHEMBL3642527
9.89	Ki	0.13	nM	CHEMBL3640401
9.89	Ki	0.13	nM	CHEMBL3642509
9.82	Ki	0.15	nM	CHEMBL3642447
9.82	Ki	0.15	nM	CHEMBL3642457
9.82	Ki	0.15	nM	CHEMBL3642502
9.80	Ki	0.16	nM	CHEMBL3642442
9.80	Ki	0.16	nM	CHEMBL3642476
9.80	Ki	0.16	nM	CHEMBL3642490
9.80	Ki	0.16	nM	CHEMBL3642491
9.77	Ki	0.17	nM	CHEMBL3640408
9.77	Ki	0.17	nM	CHEMBL3642463
9.77	Ki	0.17	nM	CHEMBL3642485
9.77	Ki	0.17	nM	CHEMBL3642512
9.74	Ki	0.18	nM	CHEMBL3640391
9.74	Ki	0.18	nM	CHEMBL3640406
9.74	Ki	0.18	nM	CHEMBL3642488
9.74	Ki	0.18	nM	CHEMBL3642495
9.74	Ki	0.18	nM	CHEMBL3642517
9.72	Ki	0.19	nM	CHEMBL3640386
9.72	Ki	0.19	nM	CHEMBL3640388
9.72	Ki	0.19	nM	CHEMBL3640389

PubChem BioAssay actives

200 with measured affinity, of 670 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[[2-(difluoromethoxy)phenyl]methyl]-6-[2-[(3R)-4-(2-hydroxyacetyl)-3-methylpiperazin-1-yl]pyrimidin-5-yl]-2,2-dimethylindol-3-one	1744286: Binding affinity to biotinylated human TNFalpha trimer (77 to 233 residues) expressed in Escherichia coli BL21(DE3) by SPR analysis	kd	0.0013	uM
8-[4-[2-[5-[(4-methylpiperazin-1-yl)methyl]-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)phenoxy]ethyl]phenyl]isoquinoline	1744286: Binding affinity to biotinylated human TNFalpha trimer (77 to 233 residues) expressed in Escherichia coli BL21(DE3) by SPR analysis	kd	0.0024	uM
(6R)-6-[(3S,5R,10S,12S,13R,14R,17R)-12-acetyloxy-3-hydroxy-4,4,10,13,14-pentamethyl-7,11,15-trioxo-1,2,3,5,6,12,16,17-octahydrocyclopenta[a]phenanthren-17-yl]-2-methyl-4-oxoheptanoic acid	1156798: Binding affinity to TNF-alpha (unknown origin)	kd	0.0024	uM
(6R)-6-[(5R,10S,12S,13R,14R,17R)-12-acetyloxy-4,4,10,13,14-pentamethyl-3,7,11,15-tetraoxo-2,5,6,12,16,17-hexahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-4-oxoheptanoic acid	1156798: Binding affinity to TNF-alpha (unknown origin)	kd	0.0027	uM
6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one	1156798: Binding affinity to TNF-alpha (unknown origin)	kd	0.0038	uM
3-[[6-[2-[(8aR)-3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-7-yl]pyrimidin-5-yl]-2,2-dimethyl-3-oxoindol-1-yl]methyl]pyridine-2-carbonitrile	1744286: Binding affinity to biotinylated human TNFalpha trimer (77 to 233 residues) expressed in Escherichia coli BL21(DE3) by SPR analysis	kd	0.0068	uM
3-[[6-[2-[(3R)-4-(2-hydroxyacetyl)-3-methylpiperazin-1-yl]pyrimidin-5-yl]-2,2-dimethyl-3-oxoindol-1-yl]methyl]pyridine-2-carbonitrile	1744286: Binding affinity to biotinylated human TNFalpha trimer (77 to 233 residues) expressed in Escherichia coli BL21(DE3) by SPR analysis	kd	0.0073	uM
(2R,6R)-2-methyl-4-oxo-6-[(3S,5R,7S,10S,13R,14R,15S,17R)-3,7,15-trihydroxy-4,4,10,13,14-pentamethyl-11-oxo-1,2,3,5,6,7,12,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl]heptanoic acid	1156798: Binding affinity to TNF-alpha (unknown origin)	kd	0.0084	uM
(2R,6R)-6-[(5R,7S,10S,13R,14R,15S,17R)-7,15-dihydroxy-4,4,10,13,14-pentamethyl-3,11-dioxo-2,5,6,7,12,15,16,17-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-4-oxoheptanoic acid	1156798: Binding affinity to TNF-alpha (unknown origin)	kd	0.0085	uM
(6R)-6-[(3S,5R,7S,10S,13R,14R,17R)-3,7-dihydroxy-4,4,10,13,14-pentamethyl-11,15-dioxo-2,3,5,6,7,12,16,17-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-4-oxoheptanoic acid	1156798: Binding affinity to TNF-alpha (unknown origin)	kd	0.0088	uM
1-[1-(4-aminophenyl)-3-tert-butylpyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	215434: Tested for inhibition of Tumor necrosis factor, alpha in THP cells	ec50	0.0090	uM
1-(3-tert-butyl-1-phenylpyrazol-5-yl)-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	215434: Tested for inhibition of Tumor necrosis factor, alpha in THP cells	ec50	0.0090	uM
(2R,3R)-1-[4-[(2-chloro-4-fluorophenyl)methoxy]phenyl]sulfonyl-N,3-dihydroxy-3-methylpiperidine-2-carboxamide	247750: Inhibitory concentration against TNF-alpha release in LPS treated whole blood	ic50	0.0104	uM
1-[1-(3-aminophenyl)-3-tert-butylpyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	215434: Tested for inhibition of Tumor necrosis factor, alpha in THP cells	ec50	0.0110	uM
(Z)-6-[(5R,7S,10S,13R,14R,15S,17R)-7,15-dihydroxy-4,4,10,13,14-pentamethyl-3,11-dioxo-2,5,6,7,12,15,16,17-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylidene-4-oxohept-5-enoic acid	1156798: Binding affinity to TNF-alpha (unknown origin)	kd	0.0129	uM
[1-[(2,5-dimethylphenyl)methyl]-6-(1-methylpyrazol-4-yl)benzimidazol-2-yl]-pyridin-4-ylmethanol	1701181: Binding affinity to human TNF measured after 2 hrs by surface plasmon resonance	kd	0.0130	uM
2-[5-[3-chloro-4-[[(1R)-1-phenylethyl]amino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0140	uM
3-chloro-N-[(1R)-1-(2-fluorophenyl)ethyl]-6-(6-methylsulfonyl-3-pyridinyl)quinolin-4-amine	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0150	uM
3-chloro-6-(2-ethoxypyrimidin-5-yl)-N-[(1R)-1-(2-fluorophenyl)ethyl]quinolin-4-amine	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0150	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[2-[(2S,6S)-2,6-dimethylmorpholin-4-yl]ethoxy]naphthalen-1-yl]urea	215434: Tested for inhibition of Tumor necrosis factor, alpha in THP cells	ec50	0.0160	uM
(5R,10S,13R,14R,17R)-17-[(2R)-7-hydroxy-6-(hydroxymethyl)hept-5-en-2-yl]-4,4,10,13,14-pentamethyl-1,2,5,6,12,15,16,17-octahydrocyclopenta[a]phenanthren-3-one	1156798: Binding affinity to TNF-alpha (unknown origin)	kd	0.0168	uM
2-[5-[3-chloro-4-[[(1R)-1-(2-fluorophenyl)ethyl]amino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0170	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	215434: Tested for inhibition of Tumor necrosis factor, alpha in THP cells	ec50	0.0180	uM
(6R)-6-[(5R,7S,10S,13R,14R,17R)-7-hydroxy-4,4,10,13,14-pentamethyl-3,11,15-trioxo-1,2,5,6,7,12,16,17-octahydrocyclopenta[a]phenanthren-17-yl]-2-methyl-4-oxoheptanoic acid	1156798: Binding affinity to TNF-alpha (unknown origin)	kd	0.0186	uM
1-[3-tert-butyl-1-(6-methyl-3-pyridinyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	215434: Tested for inhibition of Tumor necrosis factor, alpha in THP cells	ec50	0.0190	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-pyridin-4-ylethoxy)naphthalen-1-yl]urea	215434: Tested for inhibition of Tumor necrosis factor, alpha in THP cells	ec50	0.0200	uM
2-[5-[7-chloro-8-[1-(2-fluorophenyl)ethylamino]-1,5-naphthyridin-2-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0240	uM
3-chloro-6-[2-(1,1-dioxo-1,4-thiazinan-4-yl)pyrimidin-5-yl]-N-[(1R)-1-(2-fluorophenyl)ethyl]quinolin-4-amine	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0250	uM
3-[(1R)-1-[[3-chloro-7-fluoro-6-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2-methyl-1,5-naphthyridin-4-yl]amino]ethyl]-4-fluorobenzonitrile	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0250	uM
2-[5-[3-chloro-4-[1-(2-fluorophenyl)ethylamino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0270	uM
2-[5-[3-chloro-4-[1-(3-fluorophenyl)ethylamino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0310	uM
2-[5-[3-chloro-4-[1-(2-fluorophenyl)propylamino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0350	uM
5-[3-chloro-4-(2,5-dimethylanilino)quinolin-6-yl]pyridine-2-carbonitrile	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0350	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-imidazol-1-ylethoxy)naphthalen-1-yl]urea	215434: Tested for inhibition of Tumor necrosis factor, alpha in THP cells	ec50	0.0360	uM
6-bromo-3-chloro-N-(2,5-dimethylphenyl)quinolin-4-amine	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0360	uM
2-[5-[4-[[(1R)-1-(5-amino-2-fluorophenyl)ethyl]amino]-3-chloroquinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0370	uM
1-[3-tert-butyl-1-(6-methoxy-3-pyridinyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	215434: Tested for inhibition of Tumor necrosis factor, alpha in THP cells	ec50	0.0420	uM
2-[5-[3-chloro-8-fluoro-4-[1-(2-fluorophenyl)ethylamino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0460	uM
2-[4-[3-chloro-4-[[(1R)-1-(2-fluorophenyl)ethyl]amino]quinolin-6-yl]phenyl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0470	uM
3-[(1R)-1-[[3-chloro-6-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]quinolin-4-yl]amino]ethyl]-4-fluorobenzonitrile	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0480	uM
2-[5-[3-chloro-7-fluoro-4-[1-(2-fluorophenyl)ethylamino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0480	uM
(2S,3R)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’-hydroxy-3-(hydroxymethyl)-2-(4-methoxyphenyl)butanediamide	210150: Inhibitory activity against tumor necrosis factor alpha (TNF-alpha) production in LPS-stimulated human PBMCs	ic50	0.0480	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[2-(1-oxo-1,4-thiazinan-4-yl)ethoxy]naphthalen-1-yl]urea	215434: Tested for inhibition of Tumor necrosis factor, alpha in THP cells	ec50	0.0500	uM
2-[5-[3-chloro-4-(2,5-dimethylanilino)-2-methylquinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0510	uM
2-[5-[3-chloro-4-[1-[2-(trifluoromethyl)phenyl]ethylamino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0510	uM
2-[5-[3,7-dichloro-4-[1-(2-fluorophenyl)ethylamino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0540	uM
2-[5-[3-chloro-4-[[1-(2-fluorophenyl)-2-methylpropyl]amino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0570	uM
2-[5-[3-chloro-4-[1-(4-fluorophenyl)ethylamino]quinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0620	uM
8-[4-[2-(2-isoquinolin-8-ylphenoxy)ethyl]phenyl]isoquinoline	1744286: Binding affinity to biotinylated human TNFalpha trimer (77 to 233 residues) expressed in Escherichia coli BL21(DE3) by SPR analysis	kd	0.0740	uM
2-[5-[4-(benzylamino)-3-chloroquinolin-6-yl]pyrimidin-2-yl]propan-2-ol	1693252: Displacement of fluorescent labeled probe from human recombinant His-tagged TNFalpha (77 to 233 residues) expressed in Escherichia coli preincubated for 1 hr followed by fluorogenic probe addition and measured after 3 hrs by HTRF assay	ic50	0.0820	uM

CTD chemical–gene interactions

1476 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects reaction, increases abundance, affects binding, increases expression, increases activity (+10 more)	276
Resveratrol	increases expression, affects reaction, increases activity, affects expression, increases chemical synthesis (+14 more)	64
Particulate Matter	decreases reaction, affects cotreatment, increases abundance, increases expression, decreases secretion (+6 more)	61
Tetradecanoylphorbol Acetate	increases expression, increases secretion, affects reaction, increases reaction, decreases reaction (+4 more)	56
Acetylcysteine	increases expression, decreases reaction, increases reaction, increases abundance, increases activity (+8 more)	40
Dexamethasone	decreases secretion, affects cotreatment, decreases reaction, increases secretion, increases expression (+9 more)	39
Quercetin	increases reaction, increases phosphorylation, increases secretion, decreases reaction, increases abundance (+10 more)	39
SB 203580	increases stability, decreases expression, increases phosphorylation, increases cleavage, decreases reaction (+7 more)	36
lipopolysaccharide, Escherichia coli O111 B4	increases activity, decreases reaction, increases expression, increases secretion, affects cotreatment (+5 more)	29
Air Pollutants	affects cotreatment, increases expression, decreases expression, increases secretion, increases reaction (+5 more)	26
Plant Extracts	decreases reaction, increases expression, affects reaction, affects cotreatment, increases secretion (+7 more)	23
Reactive Oxygen Species	increases expression, affects response to substance, increases chemical synthesis, affects reaction, increases abundance (+6 more)	22
3-(4-methylphenylsulfonyl)-2-propenenitrile	increases secretion, increases abundance, affects localization, affects binding, increases reaction (+6 more)	21
Vehicle Emissions	affects cotreatment, affects expression, decreases expression, decreases reaction, increases abundance (+3 more)	21
Cadmium	decreases reaction, increases abundance, affects expression, affects response to substance, affects cotreatment (+6 more)	21
Dinoprostone	decreases expression, increases reaction, increases abundance, affects cotreatment, increases metabolic processing (+3 more)	21
sodium arsenite	increases expression, increases cleavage, decreases expression, decreases response to substance, increases phosphorylation (+9 more)	20
Curcumin	affects cotreatment, increases secretion, affects localization, increases phosphorylation, affects binding (+8 more)	20
Glucose	affects cotreatment, decreases expression, affects localization, increases expression, increases secretion (+5 more)	20
Hydrogen Peroxide	decreases expression, increases activity, decreases response to substance, affects cotreatment, affects localization (+7 more)	20
bisphenol A	affects cotreatment, increases expression, increases secretion, decreases reaction, decreases expression	19
Simvastatin	decreases reaction, increases expression, increases activity, increases degradation, increases secretion (+9 more)	19
pyrrolidine dithiocarbamic acid	decreases reaction, increases activity, increases degradation, decreases secretion, increases phosphorylation (+7 more)	18
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases secretion, affects cotreatment, increases expression, increases stability, decreases response to substance (+5 more)	18
Zinc	decreases reaction, affects cotreatment, increases cleavage, increases degradation, increases activity (+10 more)	18
Cadmium Chloride	decreases reaction, increases expression, increases activity, increases reaction, increases secretion (+3 more)	18
pyrazolanthrone	decreases expression, increases activity, affects cotreatment, increases phosphorylation, affects reaction (+5 more)	17
Estradiol	decreases activity, affects cotreatment, affects reaction, decreases expression, affects expression (+11 more)	17
U 0126	increases cleavage, increases activity, affects cotreatment, decreases expression, decreases reaction (+2 more)	16
Calcimycin	decreases reaction, increases expression, increases secretion, affects cotreatment	16

ChEMBL screening assays

193 unique, capped per target: 162 binding, 31 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1070178	Binding	Displacement of [125I]TNF-a from TNFalpha in human U937 cells at 10 uM after 120 mins by scintillation counting	Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist. — Bioorg Med Chem Lett
CHEMBL1737942	Functional	PUBCHEM_BIOASSAY: SAR analysis of inhibitors of TNFa specific NF-kB induction revised. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID1566, AID1575, AID1578, AID1579, AID1852, AID2469, AID2483, AID2485, AID280	PubChem BioAssay data set

Cellosaurus cell lines

12 cell lines: 5 cancer cell line, 4 embryonic stem cell, 2 transformed cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0160	B78/TNF	Cancer cell line	Male
CVCL_6924	JEG-3/VP16-TNFa	Cancer cell line	Male
CVCL_A447	KMST-6/TNF	Transformed cell line	Female
CVCL_A7N5	SEES3-1V human TNF, clone1	Embryonic stem cell	Male
CVCL_A7N6	SEES3-1V human TNF, clone2	Embryonic stem cell	Male
CVCL_A7N7	SEES3-1V human TNF, clone3	Embryonic stem cell	Male
CVCL_B1AL	Abcam THP-1 TNF KO	Cancer cell line	Male
CVCL_D6CS	HyCyte THP-1 KO-hTNF	Cancer cell line	Male
CVCL_E0RL	Ubigene HeLa TNF KO	Cancer cell line	Female
CVCL_E6S0	Genomeditech CHO-K1 H_TNF(Membrane bound)	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00286351	PHASE4	COMPLETED	Use of Arimidex and Zoladex as Pretreatment to IVF in Women With Ovarian Endometriosis
NCT00621179	PHASE4	COMPLETED	Endometrial Markers and Response of Endometriosis Patients to Prolonged GnRH Agonist Prior to IVF
NCT00625950	PHASE4	COMPLETED	Endometriosis Patients Undergoing Quinagolide Treatment
NCT00654524	PHASE4	UNKNOWN	Randomized Study of Gonadotropin-releasing-hormone Agonist (GnRH-a) or Expectant Management for Endometriosis
NCT00735852	PHASE4	COMPLETED	Decapeptyl SR With Livial Add Back Therapy in the Management of Chronic Cyclical Pelvic Pain in Pre Menopausal Women
NCT00844012	PHASE4	UNKNOWN	Continuous Postoperative Use of Low-Dose Combined Oral Contraceptivesfor for Endometriosis-Related Chronic Pelvic Pain
NCT01056042	PHASE4	COMPLETED	Efficacy of Injectable Contraceptive and Oral Contraceptive Administered After Surgical Treatment of Endometriosis With Pain
NCT01581359	PHASE4	COMPLETED	The Effect of Pre-treatment With GnRH Analogues Prior in Vitro Fertilization in Patients With Endometriosis
NCT01682642	PHASE4	COMPLETED	The Influence of Adjuvant Medical Treatment of Peritoneal Endometriosis on the Outcome of IVF. A Prospective Randomized Analysis.
NCT01769781	PHASE4	COMPLETED	Anastrazole Plus GnRH-agonist in the Treatment of Endometriosis Recurrence
NCT01779232	PHASE4	COMPLETED	Danazol Treatment in Endometriosis Women Before IVF
NCT02158845	PHASE4	COMPLETED	Levonorgestrel-releasing Intrauterine System in Patients With Endometriosis
NCT02165917	PHASE4	UNKNOWN	Study to Compare Peritoneal Ablation by Excision Only and Excision With the Use of an Adhesion Barrier
NCT02213081	PHASE4	COMPLETED	Ulipristal for Endometriosis-related Pelvic Pain
NCT02214550	PHASE4	COMPLETED	Chronic Pain Risk Associated With Menstrual Period Pain
NCT02385448	PHASE4	UNKNOWN	Comparing the Use of Dienogest and Combined Oral Contraceptive Pills (Microgynon) to Reduce the Risk of Recurrence of Endometriotic Cyst After Conservative Surgery
NCT02387931	PHASE4	COMPLETED	Supplementation in Adolescent Girls With Endometriosis
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT02427386	PHASE4	COMPLETED	Homeopathic Treatment of Chronic Pelvic Pain in Women With Endometriosis
NCT02475564	PHASE4	COMPLETED	Resveratrol for Pain Due to Endometriosis
NCT02480647	PHASE4	COMPLETED	Clinical Trial the Use of Levonorgestrel-releasing Intrauterine System Versus Etonogestrel Implant in Endometriosis
NCT02534688	PHASE4	COMPLETED	Effectiveness of Levonorgestrel-intrauterine System (LNG-IUS) Versus Depot Medroxyprogesterone Acetate (DMPA) in Treatment of Pelvic Pain in Clinically Diagnosed Endometriotic Patients
NCT02812186	PHASE4	COMPLETED	Deep Versus Moderate Neuromuscular Blockade During Laparoscopic Surgery
NCT04218487	PHASE4	UNKNOWN	Xuefu-Zhuyu Capsule for the Treatment of Qizhi Xueyu Zheng (Qi Stagnation and Blood Stasis Syndrome)
NCT04554693	PHASE4	ACTIVE_NOT_RECRUITING	The Use of Low Dose Metronidazole to Decrease Postoperative Pain After Endometriosis Surgery
NCT04942015	PHASE4	UNKNOWN	Honghuaruyi Wan for Endometriosis Dysmenorrhea
NCT05013242	PHASE4	UNKNOWN	Goserline Acetate VS Dienogest in Endometriosi
NCT05059626	PHASE4	RECRUITING	Endometriosis and Microvascular Dysfunction; Simvastatin and Duavee
NCT05331053	PHASE4	TERMINATED	MicroRNA Activation of LOX-1 Mechanisms in Endometriosis
NCT05560230	PHASE4	COMPLETED	Intraoperative Clonidine for Postoperative Pain Management in Patients Undergoing Surgical Treatment for Endometriosis
NCT05962034	PHASE4	RECRUITING	Thromboxane Function in Women With Endometriosis
NCT06523530	PHASE4	RECRUITING	Effect of a GnRH Analog on Hepatic Steatosis
NCT06543550	PHASE4	RECRUITING	Comparison Between the Effects of Implantable Gestrinone and Oral Dienogest in the Treatment of Endometriosis
NCT06577233	PHASE4	RECRUITING	Superior Hypogastric Nerve Plexus Block With Bupivacaine After Robotic Resection of Endometriosis
NCT06951802	PHASE4	RECRUITING	Endometriosis and Pain Treatment by Intraoperative Administration of Low-dose Ketamine
NCT07144904	PHASE4	NOT_YET_RECRUITING	Assessing the Efficacy of Indocyanine Green for Ureter Identification During Robot-Assisted Surgery in Advanced-Stage Endometriosis
NCT07182032	PHASE4	WITHDRAWN	Ketamine in Central Sensitization
NCT07532876	PHASE4	ENROLLING_BY_INVITATION	Comparison of Elagolix and OCPs in Reducing Endometriosis Associated Pelvic Pain
NCT00225186	PHASE3	COMPLETED	Safety and Efficacy of SH T00660AA in Treatment of Endometriosis
NCT00225199	PHASE3	COMPLETED	Efficacy and Safety of SH T00660AA in Treatment of Endometriosis