RELA

Summary

RELA (RELA proto-oncogene, NF-kB subunit, HGNC:9955) is a protein-coding gene on chromosome 11q13.1, encoding Transcription factor p65 (Q04206). NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cel…. It is a selective cancer dependency (DepMap: 27.5% of cell lines).

NF-kappa-B is a ubiquitous transcription factor involved in several biological processes. It is held in the cytoplasm in an inactive state by specific inhibitors. Upon degradation of the inhibitor, NF-kappa-B moves to the nucleus and activates transcription of specific genes. NF-kappa-B is composed of NFKB1 or NFKB2 bound to either REL, RELA, or RELB. The most abundant form of NF-kappa-B is NFKB1 complexed with the product of this gene, RELA. Four transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5970 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined immunodeficiency due to RELA haploinsufficiency (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 528 total — 31 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 27.5% of screened cell lines
• Transcription factor: yes — 589 downstream targets (CollecTRI)
• MANE Select transcript: NM_021975

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9955
Approved symbol	RELA
Name	RELA proto-oncogene, NF-kB subunit
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	p65
Ensembl gene	ENSG00000173039
Ensembl biotype	protein_coding
OMIM	164014
Entrez	5970

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 17 protein_coding, 8 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000308639, ENST00000406246, ENST00000525301, ENST00000525658, ENST00000525693, ENST00000525858, ENST00000526257, ENST00000526283, ENST00000526738, ENST00000527074, ENST00000527749, ENST00000527874, ENST00000527909, ENST00000529330, ENST00000529389, ENST00000531238, ENST00000531484, ENST00000532776, ENST00000532879, ENST00000532999, ENST00000533187, ENST00000533546, ENST00000534283, ENST00000534305, ENST00000534558, ENST00000612991, ENST00000878957, ENST00000931853, ENST00000931854, ENST00000959966, ENST00000959967

RefSeq mRNA: 11 — MANE Select: NM_021975 NM_001145138, NM_001243984, NM_001243985, NM_001404657, NM_001404658, NM_001404659, NM_001404660, NM_001404661, NM_001404662, NM_001404663, NM_021975

CCDS: CCDS31609, CCDS44651, CCDS73322

Canonical transcript exons

ENST00000406246 — 11 exons

Exon	Start	End
ENSE00002141091	65662826	65662916
ENSE00002143407	65653601	65655000
ENSE00003487967	65661687	65661835
ENSE00003534265	65658718	65658822
ENSE00003541429	65662179	65662205
ENSE00003552257	65655855	65655935
ENSE00003579803	65659666	65659797
ENSE00003649055	65658287	65658499
ENSE00003670668	65655688	65655762
ENSE00003684448	65661937	65662088
ENSE00003689993	65660124	65660215

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 96.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 96.6121 / max 861.6571, expressed in 1827 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120663	66.3718	1826
120664	23.6442	1817
120666	5.0187	1080
120665	1.1745	334
120661	0.2741	136
120662	0.1287	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	96.99	gold quality
popliteal artery	UBERON:0002250	96.93	gold quality
tibial artery	UBERON:0007610	96.93	gold quality
left uterine tube	UBERON:0001303	96.76	gold quality
cartilage tissue	UBERON:0002418	96.74	gold quality
aorta	UBERON:0000947	96.63	gold quality
right lung	UBERON:0002167	96.42	gold quality
ascending aorta	UBERON:0001496	96.39	gold quality
thoracic aorta	UBERON:0001515	96.38	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.29	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.29	gold quality
lower esophagus	UBERON:0013473	96.28	gold quality
descending thoracic aorta	UBERON:0002345	96.18	gold quality
right coronary artery	UBERON:0001625	96.16	gold quality
ectocervix	UBERON:0012249	96.16	gold quality
body of uterus	UBERON:0009853	96.13	gold quality
granulocyte	CL:0000094	96.06	gold quality
endocervix	UBERON:0000458	96.02	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.02	gold quality
left ovary	UBERON:0002119	95.97	gold quality
skin of leg	UBERON:0001511	95.96	gold quality
left coronary artery	UBERON:0001626	95.93	gold quality
upper lobe of left lung	UBERON:0008952	95.85	gold quality
right ovary	UBERON:0002118	95.79	gold quality
skin of abdomen	UBERON:0001416	95.76	gold quality
omental fat pad	UBERON:0010414	95.76	gold quality
peritoneum	UBERON:0002358	95.71	gold quality
tibial nerve	UBERON:0001323	95.70	gold quality
body of stomach	UBERON:0001161	95.60	gold quality
coronary artery	UBERON:0001621	95.56	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.61

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

589 targets.

Target	Regulation
ABCA1	Repression
ABCB1	Activation
ABCG2	Activation
ABL1
ADAM12
ADAM2
ADAMTS5
ADGRG3
ADORA1	Activation
ADORA2A	Unknown
ADORA3	Unknown
ADRA1D
AGER	Activation
AGT	Unknown
AKIP1
AKR1B1	Activation
AKT1	Repression
AKT2	Repression
ALOX5	Repression
ALOX5AP	Unknown
AMH	Activation
AMIGO2
AP1	Activation
APOE
APPL1
AQP2
AQP5
AR	Repression
ATM
ATP11C

JASPAR motifs

Motif	Name	Family
MA0107.1	RELA	NF-kappaB-related factors

JASPAR matrix evidence (PMIDs): PMID:1406630

Upstream regulators (CollecTRI, top): AGO1, AGO3, APEX1, AR, ATF2, BCL3, CEBPB, CPNE1, E2F1, EGR1, EP300, ETV3, FHL2, FOS, FOXO1, GATA3, GFI1, GSK3B, HDAC9, HOXA9, HSF1, IRF6, KAT7, KMT2A, MBD2, NCOR1, NFKB1, NFKB, NFKBIA, NOTCH1, NR1H4, NR1I2, NR3C1, NR3C2, PARP1, PGR, PPP2CB, RBPJ, REL, RELA

miRNA regulators (miRDB)

52 targeting RELA, 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-186-5P	99.99	70.83	3707
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-1251-3P	99.64	67.21	1408
HSA-MIR-888-3P	99.53	69.77	1057
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1275	99.47	67.90	2749

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 27.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Physical exercise induces activation of NF-kappaB in human peripheral blood lymphocytes (PMID:11813986)
• Respiratory syncytial virus induction of chemokine gene expression involves a redox-sensitive NF-kappaB1 signaling mechanism that differs from that mediated by TNF alpha in that it involves predominantly the RelA subunit of NF-kappaB. (PMID:11922866)
• activation and expression of nuclear factor-kappaB (NF-kappaB) and effects of anti-inflammatory treatment on NF-kappaB in the intestinal mucosa of patients with ulcerative colitis (UC) (PMID:11953203)
• MDM2 can induce expression of the p65 subunit of NF-kappaB (PMID:11964305)
• NF-KB could be considered as a coordinating element in the body’s response to stress, infection or inflammation, and it may be a good therapeutic target. (PMID:11980335)
• A novel form is induced by and forms a complex with the proto-oncogene c-Myc (PMID:12027803)
• NFkB is associated with antiestrogen resistance in breast cancer (PMID:12067985)
• C-Rel can both induce and inhibit apoptosis in HeLa cells by upregulation of MnSOD (PMID:12080470)
• NF-kappaB is regulated by the redox factor Ref-1 in the nucleus (PMID:12213807)
• Data show that interleukin-1 induces nuclear transport of RelA. (PMID:12350227)
• cross-linking FcgammaRI and -RII but not FcgammaRIII activates transcription factor NF-kappaB(p65) (PMID:12377934)
• acetylation of p65 plays a key role in IkappaBetaalpha-mediated attenuation of NF-kappaBeta transcriptional activity which is an important process that restores the latent state in post-induced cells (PMID:12419806)
• The NF-kappa B activation in lymphotoxin beta receptor signaling depends on the phosphorylation of p65 at serine 536. (PMID:12419817)
• B-oligomer of pertussis toxin inhibits HIV-1 LTR-driven transcription through suppression of NF-kappaB p65 subunit activity (PMID:12429528)
• Protein kinase C delta-NF-kappaB signaling regulates VCAM1 stimulation by thrombin in endothelial cells (PMID:12493764)
• RelA expression is regulated by replication factor C (p140) (PMID:12509469)
• S276 is the major phosphorylation site of p65 and its phosphorylation is essential for p65-dependent cellular responses (PMID:12559944)
• IkappaBalpha and p65 have roles in regulating the cytoplasmic shuttling of nuclear corepressors (PMID:12589049)
• The translocation of RelA/p65 was investigated using Western blotting and immunocytochemistry. the COX-2 inhibitor SC236 worked directly through suppressing nuclear translocation of RelA/p65. (PMID:12606945)
• Adenosine selectively suppresses TNF-induced NF-kappaB activation, which may contribute to its role in suppression of inflammation and of the immune system. (PMID:12606947)
• Inhibiting constitutive NF-kappa B activity by expressing I kappa B alpha M suppressed the tumorigenicity of a nonmetastatic human pancreatic cancer cell line, PANC-1, in an orthotopic nude mouse model. (PMID:12618762)
• Data show that increased expression of nuclear factor-kappaB (NF-kB) in amnion during labor is associated with an increase in the expression of NF-kBp65 and the NF-kB binding proteins IkBa, IkBb-1 and IkBb-2. (PMID:12651903)
• NF-kappa B induced proinflammatory & antiapoptotic genes in epithelial and mesenchymal cells of human skin. In keratinocytes, not fibroblasts, it induced p21(CIP1). GIF levls increased by NF-kappa B in both, but inhibited growth only in keratinocytes. (PMID:12673201)
• NF-kappaB has a role in the migration and the organ-specific homing of metastatic breast cancer cells (PMID:12690099)
• p65/RelA, one of the two subunits of the transcription factor NF-kappaB, binds to the BRCA1 protein. (PMID:12700228)
• SINK specifically interacted with the NF-kappaB transactivator p65 and inhibited p65 phosphorylation (PMID:12736262)
• RING finger protein AO7 supports NF-kappaB-mediated transcription by interacting with the transactivation domain of the p65 subunit. (PMID:12748188)
• Mitogenic and antiapoptotic role of constitutive NF-kappaB/Rel activity in pancreatic cancer. (PMID:12767057)
• During dendritic cell maturation, rapidly activated dimers (e.g.,RelA) bound to a subset of target promoters are gradually replaced by slowly activated dimers (e.g., RelB). (PMID:12820969)
• Primary CML blasts showed constitutive p65/RelA NF-kappaB/Rel DNA binding activity (PMID:12829026)
• IkappaB and NF-kappaB are substrates for the IKK complex in the activation of NF-kappaB (PMID:12842894)
• NFkB confers estrogen-independent growth on breast cancer (PMID:12972607)
• NFkB is part of a gene network impliceted in estrogen receptor signaling (PMID:14576841)
• Ciglitazone induced phosphorylation of PPARgamma through the MAP kinase pathway provides a potential regulatory mechanism for PPARgamma’s physical interaction with p65 (PMID:14587029)
• STAT3/NF-kappaB p65 cross-talk activated by IL-1 via TRAF6. (PMID:14593105)
• TGF-beta1 is a negative regulator of NF-kappaB p65 activation in the gut (PMID:14600158)
• overexpression of TNF-alpha downstream signaling targets, nuclear factor-kappaB (NF-kappaB)-inducing kinase (NIK) and p65 nuclear factor NF-kappaB, lowers PTEN expression (PMID:14623898)
• RelA blunts IL-4 induction in T cells during the relapse in patients with minimal change nephrotic syndrome. (PMID:14688382)
• Data show that NF-kappaB function is regulated by Pin1-mediated prolyl isomerization and ubiquitin-mediated proteolysis of its p65/RelA subunit. (PMID:14690596)
• the p65 peptide that can selectively inhibit NF-kappaB activation induced by various inflammatory stimuli, down-regulate NF-kappaB-mediated gene expression, and up-regulate apoptosis (PMID:14711835)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rela	ENSDARG00000098696
mus_musculus	Rela	ENSMUSG00000024927
rattus_norvegicus	Rela	ENSRNOG00000030888
drosophila_melanogaster	Dif	FBGN0011274
drosophila_melanogaster	dl	FBGN0260632

Paralogs (4): NFKB2 (ENSG00000077150), RELB (ENSG00000104856), NFKB1 (ENSG00000109320), REL (ENSG00000162924)

Protein

Protein identifiers

Transcription factor p65 — Q04206 (reviewed: Q04206)

Alternative names: Nuclear factor NF-kappa-B p65 subunit, Nuclear factor of kappa light polypeptide gene enhancer in B-cells 3

All UniProt accessions (16): Q04206, A0A087X0W8, E9PI38, E9PJR1, E9PJZ9, E9PKH5, E9PKV4, E9PM47, E9PMD5, E9PNK5, E9PNV4, E9PQS6, E9PRX2, E9PSE4, H0YCB4, Q2TAM5

UniProt curated annotations — full annotation on UniProt →

Function. NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The heterodimeric RELA-NFKB1 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. The NF-kappa-B heterodimeric RELA-NFKB1 and RELA-REL complexes, for instance, function as transcriptional activators. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The inhibitory effect of I-kappa-B on NF-kappa-B through retention in the cytoplasm is exerted primarily through the interaction with RELA. RELA shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Besides its activity as a direct transcriptional activator, it is also able to modulate promoters accessibility to transcription factors and thereby indirectly regulate gene expression. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells. The NF-kappa-B homodimeric RELA-RELA complex appears to be involved in invasin-mediated activation of IL-8 expression. Key transcription factor regulating the IFN response during SARS-CoV-2 infection.

Subunit / interactions. Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Homodimer; component of the NF-kappa-B p65-p65 complex. Component of the NF-kappa-B p65-p52 complex. May interact with ETHE1. Binds TLE5 and TLE1. Interacts with TP53BP2. Binds to and is phosphorylated by the activated form of either RPS6KA4 or RPS6KA5. Interacts with ING4 and this interaction may be indirect. Interacts with CARM1, USP48 and UNC5CL. Interacts with IRAK1BP1. Interacts with NFKBID. Interacts with NFKBIA. Interacts with GSK3B. Interacts with NFKBIB. Interacts with NFKBIE. Interacts with NFKBIZ. Interacts with EHMT1 (via ANK repeats). Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with HDAC3; HDAC3 mediates the deacetylation of RELA. Interacts with HDAC1; the interaction requires non-phosphorylated RELA. Interacts with CBP; the interaction requires phosphorylated RELA. Interacts (phosphorylated at ‘Thr-254’) with PIN1; the interaction inhibits p65 binding to NFKBIA. Interacts with SOCS1. Interacts with UXT. Interacts with MTDH and PHF11. Interacts with ARRB2. Interacts with NFKBIA (when phosphorylated), the interaction is direct; phosphorylated NFKBIA is part of a SCF(BTRC)-like complex lacking CUL1. Interacts with RNF25. Interacts (via C-terminus) with DDX1. Interacts with UFL1 and COMMD1. Interacts with BRMS1; this promotes deacetylation of ‘Lys-310’. Interacts with NOTCH2. Directly interacts with MEN1; this interaction represses NFKB-mediated transactivation. Interacts with AKIP1, which promotes the phosphorylation and nuclear retention of RELA. Interacts (via the RHD) with GFI1; the interaction, after bacterial lipopolysaccharide (LPS) stimulation, inhibits the transcriptional activity by interfering with the DNA-binding activity to target gene promoter DNA. Interacts (when acetylated at Lys-310) with BRD4; leading to activation of the NF-kappa-B pathway. Interacts with MEFV. Interacts with CLOCK. Interacts (via N-terminus) with CPEN1; this interaction induces proteolytic cleavage of p65/RELA subunit and inhibition of NF-kappa-B transcriptional activity. Interacts with FOXP3. Interacts with CDK5RAP3; stimulates the interaction of RELA with HDAC1, HDAC2 and HDAC3 thereby inhibiting NF-kappa-B transcriptional activity. Interacts with DHX9; this interaction is direct and activates NF-kappa-B-mediated transcription. Interacts with LRRC25. Interacts with TBX21. Interacts with KAT2A. Interacts with ZBTB7A; involved in the control by RELA of the accessibility of target gene promoters. Directly interacts with DDX3X; this interaction may trap RELA in the cytoplasm, impairing nuclear relocalization upon TNF activating signals. Interacts with PHF2. Interacts with MKRN2; the interaction leads to its polyubiquitination and proteasome-dependent degradation. Interacts with ECSIT. Interacts with RAB28; the interaction contributes to RELA transport from cytoplasm to nucleus. Interacts with FBXO16. (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein M2-1. (Microbial infection) Interacts with molluscum contagiosum virus MC132. (Microbial infection) Interacts with herpes virus 8 virus protein LANA1. (Microbial infection) Interacts with human cytomegalovirus protein UL44; this interaction prevents NF-kappa-B binding to its promoters.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Ubiquitinated by RNF182, leading to its proteasomal degradation. Degradation is required for termination of NF-kappa-B response. Polyubiquitinated via ‘Lys-29’-linked ubiquitin; leading to lysosomal degradation. Monomethylated at Lys-310 by SETD6. Monomethylation at Lys-310 is recognized by the ANK repeats of EHMT1 and promotes the formation of repressed chromatin at target genes, leading to down-regulation of NF-kappa-B transcription factor activity. Phosphorylation at Ser-311 disrupts the interaction with EHMT1 without preventing monomethylation at Lys-310 and relieves the repression of target genes. Phosphorylation at Ser-311 disrupts the interaction with EHMT1 and promotes transcription factor activity. Phosphorylation on Ser-536 stimulates acetylation on Lys-310 and interaction with CBP; the phosphorylated and acetylated forms show enhanced transcriptional activity. Phosphorylation at Ser-276 by RPS6KA4 and RPS6KA5 promotes its transactivation and transcriptional activities. Phosphorylation at Ser-75 by herpes simplex virus 1/HHV-1 inhibits NF-kappa-B activation. Reversibly acetylated; the acetylation seems to be mediated by CBP, the deacetylation by HDAC3 and SIRT2. Acetylation at Lys-122 enhances DNA binding and impairs association with NFKBIA. Acetylation at Lys-310 is required for full transcriptional activity in the absence of effects on DNA binding and NFKBIA association. Acetylation at Lys-310 promotes interaction with BRD4. Acetylation can also lower DNA-binding and results in nuclear export. Interaction with BRMS1 promotes deacetylation of Lys-310. Lys-310 is deacetylated by SIRT2. S-nitrosylation of Cys-38 inactivates the enzyme activity. Sulfhydration at Cys-38 mediates the anti-apoptotic activity by promoting the interaction with RPS3 and activating the transcription factor activity. Sumoylation by PIAS3 negatively regulates DNA-bound activated NF-kappa-B. Proteolytically cleaved within a conserved N-terminus region required for base-specific contact with DNA in a CPEN1-mediated manner, and hence inhibits NF-kappa-B transcriptional activity. Ubiquitinated by the SCF-FBXO16 E3 ubiquitin ligase, leading to proteasomal degradation.

Disease relevance. A chromosomal aberration involving ZFTA is found in more than two-thirds of supratentorial ependymomas. Translocation with ZFTA produces a ZFTA-RELA fusion protein. ZFTA-RELA translocations are potent oncogenes that probably transform neural stem cells by driving an aberrant NF-kappa-B transcription program. Autoinflammatory disease, familial, Behcet-like 3 (AIFBL3) [MIM:618287] An autosomal dominant, mucocutaneous disease characterized by chronic mucosal lesions, in absence of recurrent infections. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The transcriptional activation domain 3/TA3 does not participate in the direct transcriptional activity of RELA but is involved in the control by RELA of the accessibility of target gene promoters. Mediates interaction with ZBTB7A. The transcriptional activation domain 1/TA1 and the transcriptional activation domain 2/TA2 have direct transcriptional activation properties. The 9aaTAD motif found within the transcriptional activation domain 2 is a conserved motif present in a large number of transcription factors that is required for their transcriptional transactivation activity.

Isoforms (4)

UniProt ID	Names	Canonical?
Q04206-1	1, p65	yes
Q04206-2	2, p65 delta 2
Q04206-3	3, p65 delta
Q04206-4	4

RefSeq proteins (11): NP_001138610, NP_001230913, NP_001230914, NP_001391586, NP_001391587, NP_001391588, NP_001391589, NP_001391590, NP_001391591, NP_001391592, NP_068810* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000451	NFkB/Dor	Family
IPR002909	IPT_dom	Domain
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR011539	RHD_DNA_bind_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR030492	RHD_CS	Conserved_site
IPR030495	RelA_RHD_N	Domain
IPR032397	RHD_dimer	Domain
IPR033926	IPT_NFkappaB	Domain
IPR037059	RHD_DNA_bind_dom_sf	Homologous_superfamily

Pfam: PF00554, PF16179

UniProt features (76 total): strand 23, modified residue 19, helix 6, region of interest 5, turn 5, splice variant 4, cross-link 3, sequence conflict 3, mutagenesis site 2, short sequence motif 2, chain 1, domain 1, sequence variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

88 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6NV2	X-RAY DIFFRACTION	1.13
6QHL	X-RAY DIFFRACTION	1.2
7BI3	X-RAY DIFFRACTION	1.2
7BIQ	X-RAY DIFFRACTION	1.2
7BIW	X-RAY DIFFRACTION	1.2
7NV4	X-RAY DIFFRACTION	1.2
7NVI	X-RAY DIFFRACTION	1.2
7NWS	X-RAY DIFFRACTION	1.2
7NXS	X-RAY DIFFRACTION	1.2
7NXT	X-RAY DIFFRACTION	1.2
7NXW	X-RAY DIFFRACTION	1.2
7NXY	X-RAY DIFFRACTION	1.2
7O34	X-RAY DIFFRACTION	1.2
7O3A	X-RAY DIFFRACTION	1.2
7O59	X-RAY DIFFRACTION	1.2
6YOW	X-RAY DIFFRACTION	1.23
7NQP	X-RAY DIFFRACTION	1.24
6QHM	X-RAY DIFFRACTION	1.25
7NSV	X-RAY DIFFRACTION	1.33
6YPY	X-RAY DIFFRACTION	1.4
6YQ2	X-RAY DIFFRACTION	1.4
7BJF	X-RAY DIFFRACTION	1.4
7BJL	X-RAY DIFFRACTION	1.4
7BJW	X-RAY DIFFRACTION	1.4
7BKH	X-RAY DIFFRACTION	1.4
7NJ9	X-RAY DIFFRACTION	1.4
7NJB	X-RAY DIFFRACTION	1.4
7NK3	X-RAY DIFFRACTION	1.4
7NK5	X-RAY DIFFRACTION	1.4
7NLA	X-RAY DIFFRACTION	1.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q04206-F1	73.52	0.49

Functional residue map

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

Post-translational modifications (22): 1, 38, 38, 75, 122, 123, 218, 221, 254, 276, 281, 310, 310, 311, 435, 468, 505, 529, 536, 37 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
254	abolishes interaction with pin1.
276	loss of phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

94 pathways

ID	Pathway
R-HSA-1169091	Activation of NF-kappaB in B cells
R-HSA-1810476	RIP-mediated NFkB activation via ZBP1
R-HSA-193692	Regulated proteolysis of p75NTR
R-HSA-202424	Downstream TCR signaling
R-HSA-209560	NF-kB is activated and signals survival
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-3134963	DEx/H-box helicases activate type I IFN and inflammatory cytokines production
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-448706	Interleukin-1 processing
R-HSA-4755510	SUMOylation of immune response proteins
R-HSA-5603029	IkBA variant leads to EDA-ID
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5621575	CD209 (DC-SIGN) signaling
R-HSA-5660668	CLEC7A/inflammasome pathway
R-HSA-844456	The NLRP3 inflammasome
R-HSA-8853884	Transcriptional Regulation by VENTX
R-HSA-9020702	Interleukin-1 signaling
R-HSA-933542	TRAF6 mediated NF-kB activation
R-HSA-9660826	Purinergic signaling in leishmaniasis infection
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-9818749	Regulation of NFE2L2 gene expression
R-HSA-9860927	Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells
R-HSA-9909649	Regulation of PD-L1(CD274) transcription
R-HSA-9958825	Activation of STAT3 by cadherin engagement
R-HSA-1168372	Downstream signaling events of B Cell Receptor (BCR)
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 0 (showing top):

GO Biological Process (75): negative regulation of transcription by RNA polymerase II (GO:0000122), liver development (GO:0001889), hair follicle development (GO:0001942), defense response to tumor cell (GO:0002357), chromatin organization (GO:0006325), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), inflammatory response (GO:0006954), cellular defense response (GO:0006968), neuropeptide signaling pathway (GO:0007218), canonical NF-kappaB signal transduction (GO:0007249), positive regulation of cell population proliferation (GO:0008284), animal organ morphogenesis (GO:0009887), response to UV-B (GO:0010224), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of gene expression (GO:0010628), negative regulation of angiogenesis (GO:0016525), cytokine-mediated signaling pathway (GO:0019221), protein catabolic process (GO:0030163), response to muramyl dipeptide (GO:0032495), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), tumor necrosis factor-mediated signaling pathway (GO:0033209), negative regulation of protein sumoylation (GO:0033234), response to cytokine (GO:0034097), toll-like receptor 4 signaling pathway (GO:0034142), intracellular signal transduction (GO:0035556), cellular response to hepatocyte growth factor stimulus (GO:0035729), response to muscle stretch (GO:0035994), non-canonical NF-kappaB signal transduction (GO:0038061), vascular endothelial growth factor signaling pathway (GO:0038084), toll-like receptor TLR6:TLR2 signaling pathway (GO:0038124), prolactin signaling pathway (GO:0038161), negative regulation of protein catabolic process (GO:0042177), negative regulation of apoptotic process (GO:0043066), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), innate immune response (GO:0045087), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (27): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), RNA polymerase II core promoter sequence-specific DNA binding (GO:0000979), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coactivator binding (GO:0001223), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), protein kinase binding (GO:0019901), chromatin DNA binding (GO:0031490), ubiquitin protein ligase binding (GO:0031625), peptide binding (GO:0042277), phosphate ion binding (GO:0042301), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), actinin binding (GO:0042805), histone deacetylase binding (GO:0042826), NF-kappaB binding (GO:0051059), ankyrin repeat binding (GO:0071532), general transcription initiation factor binding (GO:0140296), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515), enzyme binding (GO:0019899), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (9): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), cytosol (GO:0005829), NF-kappaB p50/p65 complex (GO:0035525), NF-kappaB complex (GO:0071159), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-23 pathways:

Category	Pathways
CLEC7A (Dectin-1) signaling	2
C-type lectin receptors (CLRs)	2
Downstream signaling events of B Cell Receptor (BCR)	1
ZBP1(DAI) mediated induction of type I IFNs	1
p75 NTR receptor-mediated signalling	1
TCR signaling	1
p75NTR signals via NF-kB	1
Cellular Senescence	1
Fc epsilon receptor (FCERI) signaling	1
Cytosolic sensors of pathogen-associated DNA	1
Chromatin modifying enzymes	1
Adipogenesis	1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1
Toll Like Receptor 3 (TLR3) Cascade	1
Interleukin-1 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	5
cellular anatomical structure	4
defense response	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
gene expression	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
binding	2
negative regulation of DNA-templated transcription	1
gland development	1
hepaticobiliary system development	1
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
response to tumor cell	1
cellular component organization	1
RNA biosynthetic process	1
G protein-coupled receptor signaling pathway	1
intracellular signaling cassette	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
anatomical structure morphogenesis	1
animal organ development	1
response to UV	1
positive regulation of cytokine production	1
vascular endothelial growth factor production	1
regulation of vascular endothelial growth factor production	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
macromolecule catabolic process	1
protein metabolic process	1
response to nitrogen compound	1

Protein interactions and networks

STRING

5896 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RELA	NFKBIA	P25963	999
RELA	NFKBIB	Q15653	996
RELA	EP300	Q09472	994
RELA	CD40	P25942	991
RELA	NFKB1	P19838	987
RELA	NFKB2	Q00653	987
RELA	BRD4	O60885	986
RELA	CREB1	P16220	986
RELA	RELB	Q01201	985
RELA	HIF1A	Q16665	985
RELA	REL	Q04864	984
RELA	HDAC1	Q13547	982
RELA	JUN	P05412	981
RELA	PPARG	P37231	976
RELA	CHUK	O15111	969

IntAct

625 interactions, top by confidence:

A	B	Type	Score
NFKBIA	RELA	psi-mi:“MI:0915”(physical association)	0.980
RELA	NFKBIA	psi-mi:“MI:0914”(association)	0.980
RELA	NFKBIA	psi-mi:“MI:0915”(physical association)	0.980
NFKBIA	RELA	psi-mi:“MI:0914”(association)	0.980
FOS	JUN	psi-mi:“MI:2364”(proximity)	0.980
MAP3K8	NFKB1	psi-mi:“MI:0914”(association)	0.930
NFKBIA	NFKB1	psi-mi:“MI:0915”(physical association)	0.930
NFKBIA	NFKB1	psi-mi:“MI:0914”(association)	0.930
RELA	NFKB1	psi-mi:“MI:0914”(association)	0.920
RELA	NFKB1	psi-mi:“MI:0915”(physical association)	0.920
NFKBIA	RELA	psi-mi:“MI:0914”(association)	0.900
RELA	NFKBIA	psi-mi:“MI:0914”(association)	0.900
RELA	NFKBIB	psi-mi:“MI:0915”(physical association)	0.890
BRD4	RELA	psi-mi:“MI:0915”(physical association)	0.810
RELA	RPS3	psi-mi:“MI:0915”(physical association)	0.800

BioGRID (1928): RELA (Reconstituted Complex), RELA (Two-hybrid), RELA (Biochemical Activity), RELA (Biochemical Activity), RELA (Biochemical Activity), EP300 (Affinity Capture-Western), RELA (Affinity Capture-Western), RELA (Affinity Capture-Western), RELA (Affinity Capture-MS), DCD (Affinity Capture-MS), KRT5 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), POTEJ (Affinity Capture-MS), IL1RN (Affinity Capture-MS), POTEE (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JTY4, A0FIN4, D2HNW6, D3ZGB1, O88974, O94916, P01125, P01126, P15307, P16236, P23570, P31266, P53412, P97305, Q04206, Q04207, Q04864, Q04865, Q08BR4, Q12968, Q15678, Q3SZP0, Q4AE70, Q4VGL6, Q5EY87, Q5M7R9, Q5RJA1, Q5TC82, Q5U4T7, Q5XK84, Q62130, Q62728, Q66IV1, Q6DC04, Q6DFR2, Q6NRE7, Q6NUC6, Q7TQN4, Q80TJ7, Q86X55

Diamond homologs: O73630, P01125, P01126, P15307, P15330, P16236, P19838, P20749, P25799, P51509, P51510, P98149, P98150, P98152, Q00653, Q01201, Q03017, Q04206, Q04207, Q04861, Q04863, Q04864, Q04865, Q08353, Q5ZXN6, Q63369, Q6F3J0, Q7TQN4, Q91974, Q94527, Q9WTK5, A2ARS0, C9JTQ0, L7XCU0, L7XDS4, O00221, O54910, O75762, O89019, P07207

SIGNOR signaling

79 interactions.

A	Effect	B	Mechanism
MEN1	down-regulates	RELA	binding
PPP2CA	down-regulates	RELA	dephosphorylation
CHUK	“up-regulates activity”	RELA	phosphorylation
IKBKB	“up-regulates activity”	RELA	phosphorylation
IKBKE	up-regulates	RELA	phosphorylation
IKBKG	“up-regulates activity”	RELA	phosphorylation
TBK1	up-regulates	RELA	phosphorylation
RELA	up-regulates	HDAC4	binding
CREBBP	up-regulates	RELA	acetylation
EP300	up-regulates	RELA	acetylation
GSK3B	up-regulates	RELA	phosphorylation
STAT1	down-regulates	RELA	binding
CSNK2A1	“up-regulates activity”	RELA	phosphorylation
HDAC1	down-regulates	RELA	binding
PRKCZ	up-regulates	RELA	phosphorylation
RPS6KA4	up-regulates	RELA	phosphorylation
RELA	up-regulates	JUN	binding
RPGRIP1L	down-regulates	RELA	demethylation
KDM2A	down-regulates	RELA	demethylation
NSD1	up-regulates	RELA	methylation
CSN1S1	up-regulates	RELA	phosphorylation
NFKBIA	“up-regulates activity”	RELA	binding
PIM1	up-regulates	RELA	phosphorylation
CBP/p300	up-regulates	RELA	acetylation
RELA	up-regulates	CBP/p300	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 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
Formation of the canonical BAF (cBAF) complex	5	56.6×	3e-06
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	6	48.9×	6e-07
Regulation of MITF-M-dependent genes involved in pigmentation	6	28.5×	6e-06
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	5	10.5×	4e-03
Regulation of PD-L1(CD274) transcription	5	9.7×	5e-03
Senescence-Associated Secretory Phenotype (SASP)	5	8.9×	6e-03
Neddylation	8	6.8×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of G0 to G1 transition	6	69.7×	7e-08
regulation of nucleotide-excision repair	6	62.3×	1e-07
regulation of mitotic metaphase/anaphase transition	6	51.3×	3e-07
obsolete negative regulation of NF-kappaB transcription factor activity	6	37.1×	1e-06
positive regulation of double-strand break repair	6	35.6×	1e-06
regulation of G1/S transition of mitotic cell cycle	6	31.7×	2e-06
canonical NF-kappaB signal transduction	5	31.6×	3e-05
positive regulation of myoblast differentiation	5	31.6×	3e-05

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — STAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	10
Uncertain significance	229
Likely benign	212
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1063766	NM_021975.4(RELA):c.1080T>G (p.Tyr360Ter)	Pathogenic
1409152	NM_021975.4(RELA):c.113_114delinsAA (p.Cys38Ter)	Pathogenic
1452423	NM_021975.4(RELA):c.1153C>T (p.Gln385Ter)	Pathogenic
1453182	NM_021975.4(RELA):c.1416dup (p.Glu473fs)	Pathogenic
1456919	NM_021975.4(RELA):c.115G>T (p.Glu39Ter)	Pathogenic
1458783	NM_021975.4(RELA):c.853G>T (p.Glu285Ter)	Pathogenic
2026108	NM_021975.4(RELA):c.678_679del (p.Tyr227fs)	Pathogenic
2027397	NM_021975.4(RELA):c.549_550del (p.Ile183_Phe184insTer)	Pathogenic
2114288	NM_021975.4(RELA):c.1166_1184del (p.Gln389fs)	Pathogenic
2426698	NC_000011.9:g.(?65429138)(65430303_?)del	Pathogenic
2446403	NM_021975.4(RELA):c.1459del (p.His487fs)	Pathogenic
2446404	NM_021975.4(RELA):c.1006dup (p.Arg336fs)	Pathogenic
2769527	NM_021975.4(RELA):c.1300G>T (p.Gly434Ter)	Pathogenic
2806793	NM_021975.4(RELA):c.442C>T (p.Gln148Ter)	Pathogenic
2816833	NM_021975.4(RELA):c.355C>T (p.Gln119Ter)	Pathogenic
2826136	NM_021975.4(RELA):c.1220del (p.Pro407fs)	Pathogenic
2848689	NM_021975.4(RELA):c.608_609del (p.Ser203fs)	Pathogenic
3002011	NM_021975.4(RELA):c.917dup (p.Tyr306Ter)	Pathogenic
3244785	NC_000011.9:g.(?65420156)(65422230_?)del	Pathogenic
3639193	NM_021975.4(RELA):c.809_812del (p.Met270fs)	Pathogenic
3643951	NM_021975.4(RELA):c.1295_1308del (p.Gly432fs)	Pathogenic
3722991	NM_021975.4(RELA):c.431del (p.Pro144fs)	Pathogenic
3724028	NM_021975.4(RELA):c.120dup (p.Arg41fs)	Pathogenic
3724659	NM_021975.4(RELA):c.408dup (p.Asn137fs)	Pathogenic
4710766	NM_021975.4(RELA):c.1044dup (p.Tyr349fs)	Pathogenic
4722965	NM_021975.4(RELA):c.1288C>T (p.Gln430Ter)	Pathogenic
4725318	NM_021975.4(RELA):c.350dup (p.Ile118fs)	Pathogenic
4730349	NM_021975.4(RELA):c.19del (p.Leu7fs)	Pathogenic
4731955	NM_021975.4(RELA):c.31del (p.Ala11fs)	Pathogenic
617486	NM_021975.4(RELA):c.736C>T (p.Arg246Ter)	Pathogenic

SpliceAI

1985 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65654996:GGGTG:G	acceptor_gain	1.0000
11:65654997:GGTG:G	acceptor_gain	1.0000
11:65654998:GTG:G	acceptor_gain	1.0000
11:65654998:GTGC:G	acceptor_loss	1.0000
11:65654999:TG:T	acceptor_gain	1.0000
11:65655001:C:CA	acceptor_loss	1.0000
11:65655001:C:CC	acceptor_gain	1.0000
11:65655002:T:C	acceptor_loss	1.0000
11:65655682:CCTTA:C	donor_loss	1.0000
11:65655683:CTTA:C	donor_loss	1.0000
11:65655684:TTA:T	donor_loss	1.0000
11:65655685:TACCT:T	donor_loss	1.0000
11:65655686:A:AC	donor_gain	1.0000
11:65655687:C:CC	donor_gain	1.0000
11:65655687:CCTGG:C	donor_gain	1.0000
11:65655759:GGTC:G	acceptor_gain	1.0000
11:65655760:GTC:G	acceptor_gain	1.0000
11:65655761:TC:T	acceptor_gain	1.0000
11:65655762:CC:C	acceptor_gain	1.0000
11:65655762:CCTG:C	acceptor_loss	1.0000
11:65655763:C:CC	acceptor_gain	1.0000
11:65655764:T:C	acceptor_loss	1.0000
11:65655849:TCTCA:T	donor_loss	1.0000
11:65655850:CTCA:C	donor_loss	1.0000
11:65655851:TCAC:T	donor_loss	1.0000
11:65655852:CA:C	donor_loss	1.0000
11:65655853:A:AC	donor_gain	1.0000
11:65655853:ACCGC:A	donor_loss	1.0000
11:65655854:C:CA	donor_gain	1.0000
11:65655854:CCG:C	donor_gain	1.0000

AlphaMissense

3568 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65655908:C:G	R302P	1.000
11:65655909:G:T	R302S	1.000
11:65655910:T:A	K301N	1.000
11:65655910:T:G	K301N	1.000
11:65658301:T:G	Y288S	1.000
11:65658302:A:C	Y288D	1.000
11:65658302:A:G	Y288H	1.000
11:65658302:A:T	Y288N	1.000
11:65658306:G:C	F286L	1.000
11:65658306:G:T	F286L	1.000
11:65658307:A:C	F286C	1.000
11:65658307:A:G	F286S	1.000
11:65658308:A:C	F286V	1.000
11:65658308:A:G	F286L	1.000
11:65658308:A:T	F286I	1.000
11:65658321:A:C	S281R	1.000
11:65658321:A:T	S281R	1.000
11:65658322:C:A	S281I	1.000
11:65658323:T:G	S281R	1.000
11:65658335:C:G	D277H	1.000
11:65658343:C:G	R274P	1.000
11:65658344:G:C	R274G	1.000
11:65658346:C:G	R273P	1.000
11:65658349:A:C	L272R	1.000
11:65658349:A:G	L272P	1.000
11:65658349:A:T	L272Q	1.000
11:65658361:A:T	V268D	1.000
11:65658400:G:T	P255H	1.000
11:65658409:A:G	F252S	1.000
11:65658412:A:T	V251E	1.000

dbSNP variants (sampled 300 via entrez): RS1000011154 (11:65656066 T>C), RS1000142733 (11:65657034 C>CA), RS1000398241 (11:65664406 C>T), RS1000451969 (11:65664712 A>T), RS1000612003 (11:65657233 G>A), RS1000687043 (11:65658671 C>G,T), RS1000732981 (11:65662959 C>A,T), RS1000785482 (11:65663219 G>A,C), RS1001048264 (11:65664330 G>GTATTGTATTA), RS1001417509 (11:65663851 G>A), RS1001616973 (11:65663274 C>A), RS1001784014 (11:65659142 C>G), RS1002021671 (11:65663806 A>G), RS1002068927 (11:65657371 A>C,G), RS1002121181 (11:65657653 T>C)

Disease associations

OMIM: gene MIM:164014 | disease phenotypes: MIM:618287

GenCC curated gene-disease

Disease	Classification	Inheritance
combined immunodeficiency due to RELA haploinsufficiency	Definitive	Autosomal dominant
mucocutaneous ulceration, chronic	Strong	Autosomal dominant
hereditary pediatric Behçet-like disease	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
combined immunodeficiency due to RELA haploinsufficiency	Definitive	AD

Mondo (4): mucocutaneous ulceration, chronic (MONDO:0032659), childhood-onset schizophrenia (MONDO:0957430), combined immunodeficiency due to RELA haploinsufficiency (MONDO:0035694), (MONDO:0014761)

Orphanet (1): Childhood-onset schizophrenia (Orphanet:641496)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000155	Oral ulcer
HP:0002719	Recurrent infections
HP:0032564	Ileitis
HP:0032565	Vaginal mucosal ulceration

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001725_13	Inflammatory bowel disease	3.000000e-10
GCST002481_8	Acne (severe)	3.000000e-11
GCST006187_34	Diastolic blood pressure (cigarette smoking interaction)	1.000000e-09
GCST006188_39	Systolic blood pressure (cigarette smoking interaction)	8.000000e-15
GCST007621_2	Sensation seeking	3.000000e-07
GCST008916_61	Asthma	4.000000e-11
GCST008971_119	Urate levels	4.000000e-33
GCST010245_31	LDL cholesterol levels	6.000000e-09
GCST010637_18	Urate levels	9.000000e-18

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0006946	behavioural disinhibition measurement
EFO:0004531	urate measurement
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2094258 (PROTEIN COMPLEX GROUP), CHEMBL5533 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 701,445 (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
CHEMBL15870	INDOPROFEN	4	22,854
CHEMBL2348780	VAMOROLONE	4	151
CHEMBL325041	BORTEZOMIB	4	13,120
CHEMBL384467	DEXAMETHASONE	4	279,102
CHEMBL421	SULFASALAZINE	4	73,629
CHEMBL939	GEFITINIB	4	117,814
CHEMBL140	CURCUMIN	3	93,882
CHEMBL165	RESVERATROL	3	60,144
CHEMBL2141296	IXAZOMIB	3	6,022
CHEMBL4288984	WITHANOLIDE D	3	60
CHEMBL463763	TRIPTOLIDE	3	258
CHEMBL128988	FRENTIZOLE	2	189
CHEMBL15192	LAPACHONE	2	589
CHEMBL417799	SANGUINARIUM	2	8,822
CHEMBL169	URSOLIC ACID	2	20,825
CHEMBL129857	AS-602868	1	93
CHEMBL517080	WITHAFERIN A	1	3,891

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11227247	Toxicity	3	gefitinib	Non-Small Cell Lung Carcinoma;Toxic liver disease

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11227247	RELA	3	2.50	1	gefitinib

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — NF-kappa B TF proteins

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
RelA inhibitor A55	Binding	5.54	pKd
compound 11 [PMID: 30694059]	Inhibition	5.05	pIC50

Binding affinities (BindingDB)

962 measured of 1006 human assays (1013 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
MLS000042779	EC50	0.0019 nM
5,7-dihydroxy-3-(4-methoxyphenyl)-4H-chromen-4-one	EC50	0.00334 nM
MLS000545754	IC50	33.9 nM
2-[[3-(4-ethylphenyl)-1-phenyl-pyrazol-4-yl]methyl]isothiourea;hydrochloride	EC50	39.9 nM
(E)-1-phenyl-3-phenylazanyl-prop-2-en-1-one	EC50	59 nM
(E)-3-amino-2-[2-[[5-(1,3-benzodioxol-5-yl)-1,3,4-oxadiazol-2-yl]sulfanyl]acetyl]but-2-enenitrile	EC50	59 nM
2-(4-propoxyphenyl)imidazo[1,2-a]pyridine	EC50	59 nM
6-Bromo-2-(3,4-dichloro-phenyl)-imidazo[1,2-a]pyridine	EC50	62 nM
1-cyclohexyl-3-(4-propan-2-ylphenyl)urea	IC50	81.9 nM
2-(5-bromanylthiophen-2-yl)imidazo[1,2-a]pyridine	EC50	94 nM
(Z)-1-(1,3-benzodioxol-5-yl)-3-(2-bromoanilino)-2-propen-1-one	EC50	96 nM
7-(2-oxidanylidenepropylsulfanyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline-8-carbonitrile	EC50	104 nM
(4-heptoxyphenyl) pyridine-4-carboxylate	EC50	107 nM
1-(1,3-benzodioxol-5-yl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)urea	EC50	114 nM
2-(4-fluorophenyl)-5H-[1,2,4]triazol[5,1-a]isoindole	EC50	125 nM
3-(1,3-benzodioxol-5-ylmethylideneamino)-N,4-dimethyl-1,3-thiazol-2-imine	EC50	129 nM
3-(7-methyl-2-imidazo[1,2-a]pyridinyl)-1-benzopyran-2-one	EC50	137 nM
Benzo[1,3]dioxole-5-carboxylic acid benzothiazol-2-ylamide	EC50	138 nM
(3-Cyano-7-methoxy-quinolin-2-ylsulfanyl)-acetic acid ethyl ester	EC50	144 nM
N,N-dimethyl-4-[(E)-2-phenylethenyl]aniline	IC50	150 nM	US-8980954: Substituted cis- and trans-stilbenes as therapeutic agents
1-fluoro-2-[(E)-2-(4-methoxyphenyl)ethenyl]benzene	IC50	150 nM	US-8980954: Substituted cis- and trans-stilbenes as therapeutic agents
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-[4-(6-methyl-benzothiazol-2-yl)-phenyl]-propionamide	EC50	155 nM
MLS000674350	EC50	158 nM
(3-Methyl-pyridin-2-yl)-(4-pyridin-2-yl-thiazol-2-yl)-amine	EC50	160 nM
(4-heptoxyphenyl) pyridine-3-carboxylate	EC50	161 nM
(E)-3-(3-hydroxyanilino)-1-(3-methoxyphenyl)-2-propen-1-one	EC50	180 nM
(4-hexoxyphenyl) pyridine-3-carboxylate	EC50	189 nM
4-chloranyl-N-[2-(cyclohexen-1-yl)ethyl]benzamide	EC50	198 nM
MLS000775145	EC50	201 nM
4-fluoro-N-indan-5-yl-benzamide	EC50	217 nM
2-(4-keto-1,3-benzothiazin-2-yl)-N-phenyl-acetamide	EC50	220 nM
(2-phenyl-1,3-thiazol-4-yl)methyl 1-methylpyrrole-2-carboxylate	EC50	221 nM
(4-Dimethylamino-naphthalen-1-yl)-(4-dimethylamino-phenyl)-methanone	EC50	221 nM
3-[(4-ethoxyphenoxy)methyl]benzoic acid	IC50	225 nM
(E)-3-(4-methylsulfanylphenyl)-N-phenyl-prop-2-enamide	EC50	242 nM
MLS001033481	EC50	250 nM
(E)-3-(3,4-dimethylanilino)-1-(2-thienyl)prop-2-en-1-one	EC50	270 nM
4-amino-N’-[(1E)-(4-methoxyphenyl)methylene]-1,2,5-oxadiazole-3-carbohydrazonamide	EC50	272 nM
(3-Cyano-7-methoxy-quinolin-2-ylsulfanyl)-acetic acid methyl ester	EC50	295 nM
1-ethoxy-4-[(E)-2-phenylethenyl]benzene	IC50	300 nM	US-8980954: Substituted cis- and trans-stilbenes as therapeutic agents
2-[(E)-2-(2-fluorophenyl)ethenyl]quinoline	EC50	319 nM
2-(3-bromanyl-4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridine	EC50	327 nM
2-(4-chlorophenyl)-5H-[1,2,4]triazol[5,1-a]isoindole	EC50	343 nM
MLS000105932	EC50	346 nM
(Z)-3-(3-fluoroanilino)-1-(2-thienyl)prop-2-en-1-one	EC50	347 nM
7-amino-3-phenyl-6-pyrazolo[1,5-a]pyrimidinecarboxylic acid ethyl ester	EC50	356 nM
(E)-1-(2,3-dihydroindol-1-yl)-3-thiophen-2-yl-2-propen-1-one	EC50	356 nM
MLS000679548	EC50	361 nM
3-[(4-methoxyphenoxy)methyl]benzoic acid	IC50	370 nM
1-(1,3-benzothiazol-2-yl)-3-methyl-4-phenyl-1H-pyrazol-5-amine	EC50	385 nM

ChEMBL bioactivities

1067 potent at pChembl≥5 of 1342 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.60	IC50	0.025	nM	CHEMBL5080827
10.37	Kd	0.043	nM	CHEMBL329415
10.22	IC50	0.06	nM	LIPOXIN A4
9.30	IC50	0.5	nM	DEXAMETHASONE
8.72	IC50	1.9	nM	CHEMBL5532458
8.52	IC50	3	nM	CHEMBL337665
8.22	IC50	6	nM	CHEMBL4649115
8.21	IC50	6.2	nM	IXAZOMIB
8.10	IC50	8	nM	AS-602868
8.05	IC50	9	nM	CHEMBL3218828
8.05	IC50	9	nM	CHEMBL3218834
8.05	IC50	9	nM	CHEMBL3218836
8.05	EC50	9	nM	CHEMBL5279887
8.01	IC50	9.7	nM	BORTEZOMIB
8.00	IC50	10	nM	CHEMBL3218835
8.00	IC50	10	nM	TRIPTOLIDE
7.92	IC50	12	nM	CHEMBL3218824
7.92	IC50	12	nM	CHEMBL3218837
7.82	IC50	15	nM	CHEMBL4850374
7.77	IC50	17	nM	CHEMBL3218833
7.75	IC50	18	nM	CHEMBL3218831
7.70	IC50	20	nM	CHEMBL43549
7.66	IC50	22	nM	CHEMBL3218826
7.64	IC50	23	nM	CHEMBL3218823
7.60	IC50	25	nM	CHEMBL3218827
7.52	IC50	30	nM	CHEMBL552054
7.51	IC50	31	nM	URSOLIC ACID
7.50	IC50	32	nM	CHEMBL3218825
7.50	IC50	32	nM	CHEMBL4848017
7.46	IC50	35	nM	CHEMBL85822
7.44	IC50	36	nM	WITHANOLIDE D
7.42	IC50	38	nM	CHEMBL3218829
7.41	IC50	39	nM	CHEMBL3218832
7.39	IC50	41	nM	CHEMBL4852942
7.35	IC50	45	nM	CHEMBL1269181
7.35	IC50	45	nM	CHEMBL86615
7.33	IC50	47	nM	WITHAFERIN A
7.30	IC50	50	nM	CHEMBL336546
7.30	IC50	50	nM	CHEMBL132495
7.30	IC50	50	nM	CHEMBL4869263
7.28	IC50	53	nM	CHEMBL3218843
7.26	IC50	55	nM	GEFITINIB
7.26	IC50	55	nM	CHEMBL3234472
7.25	IC50	56	nM	CHEMBL3234471
7.23	IC50	59	nM	CHEMBL4859862
7.23	EC50	59	nM	CHEMBL1322308
7.23	EC50	59	nM	CHEMBL1384554
7.23	EC50	59	nM	CHEMBL3197844
7.23	EC50	59	nM	CHEMBL1452672
7.21	IC50	62	nM	CHEMBL3218821

PubChem BioAssay actives

280 with measured affinity, of 1998 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
methyl (E,5S,6R)-5,6-dihydroxy-8-[3-[(1R)-1-hydroxyhexyl]quinoxalin-2-yl]oct-7-enoate	1817450: Inhibition of LPS-induced NF-kappaB activation in human THP-1 monocytes expressing luciferase gene pretreated for 30 mins followed by LPS stimulation and measured after 24 hrs by bioluminescence analysis	ic50	<0.0001	uM
methyl (E,5S,6R)-5,6-dihydroxy-8-[3-[(1S)-1-hydroxyhexyl]quinoxalin-2-yl]oct-7-enoate	1817450: Inhibition of LPS-induced NF-kappaB activation in human THP-1 monocytes expressing luciferase gene pretreated for 30 mins followed by LPS stimulation and measured after 24 hrs by bioluminescence analysis	ic50	<0.0001	uM
(5S,6R,7E,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoic acid	1817450: Inhibition of LPS-induced NF-kappaB activation in human THP-1 monocytes expressing luciferase gene pretreated for 30 mins followed by LPS stimulation and measured after 24 hrs by bioluminescence analysis	ic50	0.0001	uM
Dexamethasone	2131645: Inhibition of NF-kappaB (unknown origin)	ic50	0.0005	uM
N-methyl-N-[3-methyl-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxycyclobutyl]prop-2-enamide	2064208: Inhibition of NF-kappaB activation in human TMD8 cells assessed as reduction in nucleus translocation	ic50	0.0019	uM
1-[(6-methoxy-2-thiophen-2-ylquinazolin-4-yl)amino]-3-methylpyrrole-2,5-dione	1178334: Inhibition of NF-kappaB-mediated transcriptional activation in human Jurkat cells by luciferase reporter gene assay	ic50	0.0030	uM
3-[5-[3-[2,4-dihydroxy-5-(2-methylbut-3-en-2-yl)benzoyl]-6-hydroxy-1-benzofuran-2-yl]-2,4-dihydroxyphenyl]-7-hydroxy-6-(2-methylbut-3-en-2-yl)chromen-2-one	1663477: Inhibition of NF-kappaB p65 in human HeLa cells nuclear extract by chemiluminescent assay	ic50	0.0060	uM
1-[(5-methoxy-2-thiophen-2-ylquinazolin-4-yl)amino]-3-methylpyrrole-2,5-dione	1178334: Inhibition of NF-kappaB-mediated transcriptional activation in human Jurkat cells by luciferase reporter gene assay	ic50	0.0080	uM
1-N-[2-(4-phenoxyphenyl)ethyl]phthalazine-1,7-diamine	1922378: Inhibition of NFkappaB in human Jurkat cells incubated for 30 mins by bright-glo luciferase assay	ec50	0.0090	uM
(1S,2S,4S,5S,7R,8R,9S,11S,13S)-8-hydroxy-1-methyl-7-propan-2-yl-3,6,10,16-tetraoxaheptacyclo[11.7.0.02,4.02,9.05,7.09,11.014,18]icos-14(18)-en-17-one	2075668: Inhibition of NF-kappaB (unknown origin)	ic50	0.0100	uM
(1S,2R,6S,7R,9R,11S,12S,15R,16S)-15-[(1S)-1-[(2R)-5-ethyl-4-methyl-6-oxo-2,3-dihydropyran-2-yl]ethyl]-6-hydroxy-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0150	uM
ethyl 4-[(3-methyl-2,5-dioxopyrrol-1-yl)amino]-2-thiophen-2-ylpyrimidine-5-carboxylate	1178334: Inhibition of NF-kappaB-mediated transcriptional activation in human Jurkat cells by luciferase reporter gene assay	ic50	0.0200	uM
(1’S,3’R,5’S,7’R,10’R,12’R,14’R,15’S,18’R,19’R,22’S,23’R)-10’,22’-dihydroxy-14’-(hydroxymethyl)-7’,18’-dimethyl-19’-(5-oxo-2H-furan-3-yl)spiro[1,3-thiazolidine-2,9’-4,6,11-trioxahexacyclo[12.11.0.03,12.05,10.015,23.018,22]pentacosane]-4-one	1142307: Inhibition of NF-kappaB transactivation in TNF-alpha-stimulated human K562 cells preincubated for 2 hrs followed by TNF-alpha challenge measured after 6 hrs by dual luciferase reporter gene assay	ic50	0.0300	uM
(1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid	1398545: Inhibition of biotinylated consensus sequence binding to NF-kB p65 in human HeLa nuclear extracts after 3 hrs by ELISA	ic50	0.0310	uM
[(1S,2R,6S,7S,9R,11S,12S,15S,16S)-15-[(1R)-1-[(2R)-4,5-dimethyl-6-oxo-2,3-dihydropyran-2-yl]-1-hydroxyethyl]-2,16-dimethyl-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-6-yl] acetate	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0320	uM
ethyl 4-ethyl-2-[methyl-(3-methyl-2,5-dioxopyrrol-1-yl)amino]pyrimidine-5-carboxylate	1178334: Inhibition of NF-kappaB-mediated transcriptional activation in human Jurkat cells by luciferase reporter gene assay	ic50	0.0350	uM
(1S,2R,6S,7R,9R,11S,12S,15S,16S)-15-[(1R)-1-[(2R)-4,5-dimethyl-6-oxo-2,3-dihydropyran-2-yl]-1-hydroxyethyl]-6-hydroxy-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0360	uM
(1S,2R,6S,7R,9R,11R,12R,16R)-15-[(1R)-1-[(2R,4S)-4,5-dimethyl-6-oxooxan-2-yl]-1-hydroxyethyl]-6,12-dihydroxy-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadeca-4,14-dien-3-one	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0410	uM
ethyl 2-[(3-methyl-2,5-dioxopyrrol-1-yl)amino]-4-(5-methylthiophen-2-yl)pyrimidine-5-carboxylate	1178334: Inhibition of NF-kappaB-mediated transcriptional activation in human Jurkat cells by luciferase reporter gene assay	ic50	0.0450	uM
(1S,2R,6S,7R,9R,11S,12S,15R,16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-2,3-dihydropyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0470	uM
N-[3,5-bis(trifluoromethyl)phenyl]-2-chloro-4-methylpyrimidine-5-carboxamide	1178334: Inhibition of NF-kappaB-mediated transcriptional activation in human Jurkat cells by luciferase reporter gene assay	ic50	0.0500	uM
[(1S,2R,6S,7S,9R,11R,12S,13R,15S,16S)-6-acetyloxy-15-[(1R)-1-[(2R)-4,5-dimethyl-6-oxo-2,3-dihydropyran-2-yl]-1-hydroxyethyl]-2,16-dimethyl-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-13-yl] acetate	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0500	uM
N-[3,5-bis(trifluoromethyl)phenyl]-2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxamide	1178334: Inhibition of NF-kappaB-mediated transcriptional activation in human Jurkat cells by luciferase reporter gene assay	ic50	0.0500	uM
Gefitinib	1689696: Inhibition of NFkappaB p65 in human RPMI-8226 cells incubated for 2 hrs by ELISA	ic50	0.0550	uM
[(2R)-2-[(1S)-1-[(1S,2R,6S,7S,9R,11S,12S,15R,16S)-6-acetyloxy-2,16-dimethyl-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-15-yl]ethyl]-4-methyl-6-oxo-2,3-dihydropyran-5-yl]methyl acetate	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0550	uM
[(1S,2R,6S,7S,9R,11S,12S,15R,16S)-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-2,3-dihydropyran-2-yl]ethyl]-2,16-dimethyl-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-6-yl] acetate	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0560	uM
[(1S,2R,6R,7S,9R,11S,12S,15S,16S)-15-[(1R)-1-[(2R)-4,5-dimethyl-6-oxo-2,3-dihydropyran-2-yl]-1-hydroxyethyl]-2,16-dimethyl-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-6-yl] acetate	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0590	uM
[(2R)-2-[(1S)-1-[(1S,2R,7R,9R,11S,12S,14S,15R,16S)-6-hydroxy-2,14,16-trimethyl-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-15-yl]ethyl]-4-methyl-6-oxo-2,3-dihydropyran-5-yl]methyl acetate	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0630	uM
(1S,4S,7S,10S,13R,16R)-21-hydroxy-7-[(4-methoxyphenyl)methyl]-2,4,8,10,13,31-hexamethyl-23-oxa-2,5,8,11,14,31-hexazatetracyclo[14.13.2.118,22.124,28]tritriaconta-18(33),19,21,24,26,28(32)-hexaene-3,6,9,12,15,30-hexone	1772488: Inhibition of NF-kB (unknown origin) expressed in HEK293T cells transfected with pTK-Renilla reporter preincubated for 6 hrs followed by addition of TNF-alpha and measured after 8 hrs by Dual luciferase reporter assay	ic50	0.0650	uM
Vamorolone	2075668: Inhibition of NF-kappaB (unknown origin)	ic50	0.0659	uM
(1R,2R,3S,3aR,8bS)-1,8b-dihydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3-dihydro-1H-cyclopenta[b][1]benzofuran-2-carboxamide	1398545: Inhibition of biotinylated consensus sequence binding to NF-kB p65 in human HeLa nuclear extracts after 3 hrs by ELISA	ic50	0.0700	uM
[(2R)-2-[(1S)-1-[(1S,2R,6S,7R,9R,11S,12S,15R,16S)-6-hydroxy-2,16-dimethyl-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-15-yl]ethyl]-4-methyl-6-oxo-2,3-dihydropyran-5-yl]methyl acetate	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0700	uM
(1S,2R,7R,9R,11S,12S,15S,16S)-15-[(1R)-1-[(2R)-4,5-dimethyl-6-oxo-2,3-dihydropyran-2-yl]-1-hydroxyethyl]-6-hydroxy-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0710	uM
(1S,2R,6S,7R,9R,11S,12S,14S,15R,16S)-15-[(1R)-1-[(2R,4S,5R)-4,5-dimethyl-6-oxooxan-2-yl]-1-hydroxyethyl]-6,14-dihydroxy-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0740	uM
[(2R)-2-[(1S)-1-[(1S,2R,5S,6S,7R,9R,11S,12S,15R,16S)-5-acetyloxy-6-hydroxy-2,16-dimethyl-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadecan-15-yl]ethyl]-4-methyl-6-oxo-2,3-dihydropyran-5-yl]methyl acetate	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0800	uM
Bortezomib	1762748: Inhibition of TNFalpha-induced NFkappaB activation in HEK293 cells assessed as luciferase expression by luciferase reporter activity assay	ic50	0.0850	uM
[(2R)-2-[(1S)-1-[(8S,9S,10R,13S,14S,17R)-10,13-dimethyl-1,4-dioxo-8,9,11,12,14,15,16,17-octahydro-7H-cyclopenta[a]phenanthren-17-yl]ethyl]-4-methyl-6-oxo-2,3-dihydropyran-5-yl]methyl acetate	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0950	uM
(1S,2S,3’R,4S,4’R,8S,10S,13S,14R,18S,19R,21R)-8,18-dihydroxy-3’,4’,8,10,14-pentamethylspiro[5,20-dioxahexacyclo[11.9.0.02,10.04,9.014,19.019,21]docos-16-ene-6,5’-oxolane]-2’,15-dione	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.0950	uM
1-[[5-benzoyl-4-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methylpyrrole-2,5-dione	1178334: Inhibition of NF-kappaB-mediated transcriptional activation in human Jurkat cells by luciferase reporter gene assay	ic50	0.0980	uM
ethyl 4-[(3-methyl-2,5-dioxopyrrol-1-yl)amino]-2-phenylpyrimidine-5-carboxylate	1178334: Inhibition of NF-kappaB-mediated transcriptional activation in human Jurkat cells by luciferase reporter gene assay	ic50	0.1000	uM
ethyl 4-[(3-methyl-2,5-dioxopyrrol-1-yl)amino]-2-thiophen-3-ylpyrimidine-5-carboxylate	95093: Inhibition of NF-kB mediated transcriptional activation in Jurkat T-cells	ic50	0.1000	uM
[(2R)-2-[(1S)-1-[(1S,2R,7S,9R,11S,12S,15R,16S)-6-acetyloxy-2,16-dimethyl-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-15-yl]ethyl]-4-methyl-6-oxo-2,3-dihydropyran-5-yl]methyl acetate	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.1020	uM
(1S,2R,7R,9R,11S,12S,14S,15R,16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-2,3-dihydropyran-2-yl]ethyl]-2,14,16-trimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.1270	uM
(1S,2R,6S,7R,9R,11S,12S,15R,16S)-15-[(1S)-1-[(2R,4S,5R)-4,5-dimethyl-6-oxooxan-2-yl]-1-hydroxyethyl]-6,15-dihydroxy-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.1330	uM
(E)-1-[1-(4-chlorophenyl)-5-methyltriazol-4-yl]-3-(3,4-dimethoxyphenyl)prop-2-en-1-one	1689696: Inhibition of NFkappaB p65 in human RPMI-8226 cells incubated for 2 hrs by ELISA	ic50	0.1340	uM
(1S,2R,7S,9R,11S,12S,15S,16S)-15-[(1R)-1-[(2R)-4,5-dimethyl-6-oxo-2,3-dihydropyran-2-yl]-1-hydroxyethyl]-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one	1771376: Inhibition of TNF-alpha stimulated NF-KappaB in human HEK293 cells transfected with NF-kappaB-Luc incubated for 5 hrs by luciferase reporter gene assay	ic50	0.1460	uM
2-chloro-8-(trifluoromethyl)-6H-pyrimido[4,5-b][1,5]benzothiazepin-5-one	1178334: Inhibition of NF-kappaB-mediated transcriptional activation in human Jurkat cells by luciferase reporter gene assay	ic50	0.2000	uM
N-(6-benzoyl-1H-benzimidazol-2-yl)-2-(1-thieno[3,2-d]pyrimidin-4-ylpiperidin-4-yl)-1,3-thiazole-4-carboxamide	1864336: Inhibition of NF kappa B activation (unknown origin)	ic50	0.2000	uM
3-(2-methoxyphenyl)-2-[2-(methylamino)-4-phenyl-1,3-thiazol-5-yl]quinazolin-4-one	1178339: Inhibition of NF-kappaB-mediated transcriptional activation in HEK293 cells by luciferase reporter gene assay	ic50	0.2000	uM
3-methyl-1-[[5-(4-methyl-1,3-oxazol-2-yl)-2-thiophen-2-ylpyrimidin-4-yl]amino]pyrrole-2,5-dione	95093: Inhibition of NF-kB mediated transcriptional activation in Jurkat T-cells	ic50	0.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects binding, increases phosphorylation, affects cotreatment, decreases reaction, increases activity (+10 more)	89
Resveratrol	increases reaction, affects binding, decreases reaction, increases localization, decreases activity (+11 more)	54
Tetradecanoylphorbol Acetate	decreases reaction, increases activity, increases phosphorylation, affects localization, increases localization (+7 more)	50
Acetylcysteine	affects localization, affects binding, increases activity, affects reaction, decreases phosphorylation (+11 more)	39
Arsenic Trioxide	affects expression, decreases expression, affects cotreatment, decreases activity, decreases response to substance (+11 more)	33
sodium arsenite	affects expression, decreases response to substance, decreases reaction, increases phosphorylation, affects cotreatment (+11 more)	31
Particulate Matter	affects response to substance, decreases expression, increases activity, affects binding, decreases reaction (+9 more)	31
Curcumin	decreases reaction, affects binding, increases reaction, affects cotreatment, increases activity (+10 more)	30
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases reaction, increases phosphorylation, increases reaction, affects localization, decreases phosphorylation (+5 more)	29
Hydrogen Peroxide	affects binding, increases abundance, increases localization, increases phosphorylation, increases expression (+11 more)	27
Doxorubicin	decreases response to substance, increases activity, decreases expression, increases response to substance, affects cotreatment (+13 more)	22
Quercetin	decreases reaction, affects binding, decreases expression, increases expression, increases phosphorylation (+8 more)	20
Glucose	increases phosphorylation, affects binding, increases reaction, decreases phosphorylation, affects cotreatment (+8 more)	18
pyrrolidine dithiocarbamic acid	decreases reaction, increases phosphorylation, increases activity, affects binding, decreases activity (+6 more)	17
bisphenol A	affects binding, affects folding, increases reaction, decreases expression, decreases reaction (+4 more)	16
Cisplatin	decreases expression, decreases response to substance, increases expression, decreases phosphorylation, increases degradation (+9 more)	15
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects localization, decreases reaction, increases phosphorylation, affects binding, decreases phosphorylation (+6 more)	13
Plant Extracts	decreases expression, affects localization, increases phosphorylation, increases expression, decreases phosphorylation (+3 more)	13
Cadmium Chloride	increases glutathionylation, increases localization, increases abundance, affects localization, decreases expression (+4 more)	13
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases activity, affects binding, increases localization, decreases activity (+5 more)	11
SB 203580	affects reaction, increases expression, affects localization, affects expression, decreases reaction (+3 more)	11
Bortezomib	affects cotreatment, decreases activity, decreases expression, increases activity, increases reaction (+5 more)	11
Cadmium	decreases reaction, affects cotreatment, increases expression, affects localization, increases abundance (+3 more)	11
Glucosamine	decreases reaction, increases phosphorylation, increases localization, increases expression, increases degradation	11
pyrazolanthrone	affects expression, affects reaction, increases localization, affects localization, decreases reaction (+3 more)	10
Oxygen	decreases reaction, increases expression, increases reaction, increases phosphorylation, affects response to substance (+4 more)	10
Paraquat	affects localization, affects binding, decreases reaction, increases reaction, increases activity (+3 more)	10
U 0126	increases phosphorylation, increases activity, affects cotreatment, decreases reaction, increases reaction (+6 more)	9
Calcimycin	affects cotreatment, affects localization, decreases reaction, increases activity, increases response to substance (+2 more)	9
Vehicle Emissions	affects cotreatment, decreases expression, decreases reaction, affects localization, affects binding (+6 more)	9

ChEMBL screening assays

422 unique, capped per target: 417 binding, 4 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1613870	Functional	PUBCHEM_BIOASSAY: Name: High Throughput Screen to Identify Compounds that increase expression of NF-kB in Human Neuronal Cells - Dose Response. (Class of assay: confirmatory) [Related pubchem assays: 1239 ]	PubChem BioAssay data set
CHEMBL3223786	Binding	Inhibition of NFkappaB in human FRT-Jurkat cells expressing GFP assessed as reduction of TNF expression at 10 uM after 24 hrs by flow cytometry relative to control	Novel thalidomide analogues with potent NFB and TNF expression inhibition — Medchemcomm
CHEMBL4373835	ADMET	Induction of NF-kappaB p65 phosphorylation in human HK2 cells at 4 uM by Western blot analysis	Design, synthesis and evaluation of PD176252 analogues for ameliorating cisplatin-induced nephrotoxicity. — Medchemcomm

Cellosaurus cell lines

17 cell lines: 12 cancer cell line, 3 transformed cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4GX	SAM iPSC clone 1	Induced pluripotent stem cell	Female
CVCL_A4GY	SAM iPSC clone 2	Induced pluripotent stem cell	Female
CVCL_AW41	K562 eGFP-RELA	Cancer cell line	Female
CVCL_B2DL	Abcam HeLa RELA KO	Cancer cell line	Female
CVCL_B8NR	Abcam HCT 116 RELA KO	Cancer cell line	Male
CVCL_B9B3	Abcam MCF-7 RELA KO	Cancer cell line	Female
CVCL_B9R3	Abcam A-549 RELA KO	Cancer cell line	Male
CVCL_C9AQ	HeLa RelA-mNeonGreen	Cancer cell line	Female
CVCL_D7ZC	Ubigene A-549 RELA KO	Cancer cell line	Male
CVCL_D8UI	Ubigene HCT 116 RELA KO	Cancer cell line	Male

Clinical trials (associated diseases)

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