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

DTT Name Nuclear factor NF-kappa-B (NFKB)
Synonyms Nuclear factor of kappa light polypeptide gene enhancer in B-cells; DNA-binding factor KBF
Gene Name NFKB1
DTT Type
Successful target
[1]
UniProt ID
NFKB1_HUMAN ; NFKB2_HUMAN ; TF65_HUMAN ; RELB_HUMAN ; REL_HUMAN
TTD ID
T83145
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MAEDDPYLGRPEQMFHLDPSLTHTIFNPEVFQPQMALPTDGPYLQILEQPKQRGFRFRYV
CEGPSHGGLPGASSEKNKKSYPQVKICNYVGPAKVIVQLVTNGKNIHLHAHSLVGKHCED
GICTVTAGPKDMVVGFANLGILHVTKKKVFETLEARMTEACIRGYNPGLLVHPDLAYLQA
EGGGDRQLGDREKELIRQAALQQTKEMDLSVVRLMFTAFLPDSTGSFTRRLEPVVSDAIY
DSKAPNASNLKIVRMDRTAGCVTGGEEIYLLCDKVQKDDIQIRFYEEEENGGVWEGFGDF
SPTDVHRQFAIVFKTPKYKDINITKPASVFVQLRRKSDLETSEPKPFLYYPEIKDKEEVQ
RKRQKLMPNFSDSFGGGSGAGAGGGGMFGSGGGGGGTGSTGPGYSFPHYGFPTYGGITFH
PGTTKSNAGMKHGTMDTESKKDPEGCDKSDDKNTVNLFGKVIETTEQDQEPSEATVGNGE
VTLTYATGTKEESAGVQDNLFLEKAMQLAKRHANALFDYAVTGDVKMLLAVQRHLTAVQD
ENGDSVLHLAIIHLHSQLVRDLLEVTSGLISDDIINMRNDLYQTPLHLAVITKQEDVVED
LLRAGADLSLLDRLGNSVLHLAAKEGHDKVLSILLKHKKAALLLDHPNGDGLNAIHLAMM
SNSLPCLLLLVAAGADVNAQEQKSGRTALHLAVEHDNISLAGCLLLEGDAHVDSTTYDGT
TPLHIAAGRGSTRLAALLKAAGADPLVENFEPLYDLDDSWENAGEDEGVVPGTTPLDMAT
SWQVFDILNGKPYEPEFTSDDLLAQGDMKQLAEDVKLQLYKLLEIPDPDKNWATLAQKLG
LGILNNAFRLSPAPSKTLMDNYEVSGGTVRELVEALRQMGYTEAIEVIQAASSPVKTTSQ
AHSLPLSPASTRQQIDELRDSDSVCDSGVETSFRKLSFTESLTSGASLLTLNKMPHDYGQ
EGPLEGKI
Function
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 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. 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. In a non-canonical activation pathway, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. The NF-kappa-B heterodimeric RelB-p52 complex is a transcriptional activator. The NF-kappa-B p52-p52 homodimer is a transcriptional repressor. NFKB2 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p100 and generation of p52 by a cotranslational processing. The proteasome-mediated process ensures the production of both p52 and p100 and preserves their independent function. p52 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. p52 and p100 are respectively the minor and major form; the processing of p100 being relatively poor. Isoform p49 is a subunit of the NF-kappa-B protein complex, which stimulates the HIV enhancer in synergy with p65. In concert with RELB, regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-ARNTL/BMAL1 heterodimer. 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.
KEGG Pathway
MAPK signaling pathway (hsa04010 )
NF-kappa B signaling pathway (hsa04064 )
Osteoclast differentiation (hsa04380 )
Legionellosis (hsa05134 )
HTLV-I infection (hsa05166 )
Epstein-Barr virus infection (hsa05169 )
Pathways in cancer (hsa05200 )
Viral carcinogenesis (hsa05203 )
Reactome Pathway
DEx/H-box helicases activate type I IFN and inflammatory cytokines production (R-HSA-3134963 )
TAK1 activates NFkB by phosphorylation and activation of IKKs complex (R-HSA-445989 )
Interleukin-1 processing (R-HSA-448706 )
IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR) (R-HSA-5603027 )
IkBA variant leads to EDA-ID (R-HSA-5603029 )
Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761 )
NIK-->noncanonical NF-kB signaling (R-HSA-5676590 )
TRAF6 mediated NF-kB activation (R-HSA-933542 )
RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
1 Approved Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Sulfasalazine DMICA9H Irritable bowel syndrome DD91.0 Approved [1]
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14 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Edasalonexent DMYVBF6 Duchenne dystrophy 8C70 Phase 3 [2]
Laquinimod DM3IWS8 Lupus 4A40 Phase 3 [3]
MD1003 DMVZ57G Multiple sclerosis 8A40 Phase 3 [2]
Triptolide DMCMDVR Autoimmune diabetes 5A10 Phase 3 [4]
CAT 1004 DMQBP7R Duchenne dystrophy 8C70 Phase 2 [5]
CZEN-002 DMUDMHA Fungal infection 1F29-1F2F Phase 2 [6]
L-ornithine phenylacetate DM0GZTD Acute liver failure DB91 Phase 2 [7]
Parthenolide DMCQBFT N. A. N. A. Phase 2 [8]
PRO22 DMMEL6B Atopic dermatitis EA80 Phase 2 [9]
Recoflavone DMCSR8I Inflammatory bowel disease DD72 Phase 2 [10]
Vadimezan DMK7CYX Solid tumour/cancer 2A00-2F9Z Phase 2 [11]
XP-23829 DMELUYN Multiple sclerosis 8A40 Phase 2 [12]
Avrina DMRS58M Skin infection 1F28-1G0Z Phase 1/2 [7]
LC-1 DMJEACT Acute myeloid leukaemia 2A60 Phase 1 [13]
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⏷ Show the Full List of 14 Clinical Trial Drug(s)
41 Patented Agent(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
1-hydroxyl-3,5-bis(4-hydroxylstyryl)benzene derivative 1 DMK75BT Muscular wasting 8C7Y Patented [14]
1-hydroxyl-3,5-bis(4-hydroxylstyryl)benzene derivative 2 DMIWQZ5 Muscular wasting 8C7Y Patented [14]
1-hydroxyl-3,5-bis(4-hydroxylstyryl)benzene derivative 3 DMNXAUZ Muscular wasting 8C7Y Patented [14]
1-hydroxyl-3,5-bis(4-hydroxylstyryl)benzene derivative 4 DMV2W9Z Muscular wasting 8C7Y Patented [14]
N-quinolin-benzene sulphonamide derivative 1 DMLSK97 N. A. N. A. Patented [14]
N-quinolin-benzene sulphonamide derivative 2 DMH65CX N. A. N. A. Patented [14]
N-quinolin-benzene sulphonamide derivative 3 DMU65YX N. A. N. A. Patented [14]
Olenolic acid acetate derivative 1 DMZIALN N. A. N. A. Patented [14]
PMID25553724-Compound-EP20132578214 2 DM4GQJH N. A. N. A. Patented [14]
PMID25553724-Compound-US2011000295210 DMM3QEW Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2011788838110 DMZCO6J Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2011796857710 DMH4DMY Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2011799419010 DMIZ64O Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2011801300410 DMZ96CG Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2011803494010 DMCDHZT Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2011806744710 DMIAV5M Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2012810604610 DM9KAF1 Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2012819831110 DMS7RYP Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2012820715110 DMDQ6H7 Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2012830453910 DMCUMSV Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US2012832440110 DMFCE51 Immune System disease 4A01-4B41 Patented [14]
PMID25553724-Compound-US20130116324 2 DMUBZO3 N. A. N. A. Patented [14]
PMID25553724-Compound-US20138552206 4 DMV7SQH N. A. N. A. Patented [14]
PMID25553724-Compound-US20138552206 5 DMRVE7Z N. A. N. A. Patented [14]
PMID25553724-Compound-WO2011127048 31 DM5ATIV N. A. N. A. Patented [14]
PMID25553724-Compound-WO2011127048 32 DMH3NOZ N. A. N. A. Patented [14]
PMID25553724-Compound-WO2011127048 33 DMH7496 N. A. N. A. Patented [14]
PMID25553724-Compound-WO2011127048 34 DM4YE8W N. A. N. A. Patented [14]
PMID25553724-Compound-WO2011152671 2 DMPQ175 N. A. N. A. Patented [14]
PMID25553724-Compound-WO2013082253 31 DMPFMSJ N. A. N. A. Patented [14]
PMID25553724-Compound-WO2013082253 32 DMXYSO1 N. A. N. A. Patented [14]
PMID25553724-Compound-WO2013082253 33 DMR1YH9 N. A. N. A. Patented [14]
PMID25553724-Compound-WO2013082253 34 DML1U69 N. A. N. A. Patented [14]
Quinoxaline derivative 1 DMENQ5O N. A. N. A. Patented [14]
Quinoxaline derivative 2 DM031YW N. A. N. A. Patented [14]
Quinoxaline derivative 3 DMLZRAI N. A. N. A. Patented [14]
Quinoxaline derivative 4 DMS3PRT N. A. N. A. Patented [14]
Quinoxaline derivative 5 DM8EY2G N. A. N. A. Patented [14]
Quinoxaline derivative 6 DMBRX8D N. A. N. A. Patented [14]
Tihotungstate derivative 1 DM5UI73 Aberrant vascularization BE2Z Patented [14]
Tihourea derivative 1 DMGR6IJ N. A. N. A. Patented [14]
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⏷ Show the Full List of 41 Patented Agent(s)
7 Discontinued Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
P-1 DMFNLDY Atopic dermatitis EA80 Discontinued in Phase 3 [15]
AS602868 DMKXDOI Multiple myeloma 2A83 Discontinued in Phase 1 [16]
SIM-916 DMTGCSX Gynecological disease GA6Z Discontinued in Phase 1 [7]
Gliotoxin DMONQYZ N. A. N. A. Terminated [17]
HELENALIN DMMCI4H N. A. N. A. Terminated [18]
MOL-218 DM543VY Asthma CA23 Terminated [19]
Tyloxapol DMR3S9B Congenital alveolar dysplasia Terminated [20]
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⏷ Show the Full List of 7 Discontinued Drug(s)
50 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
15-ACETOXY-EREMANTHOLIDE B DMLSZW2 Discovery agent N.A. Investigative [18]
15-DEOXYBUDLEIN A DMJC0NQ Discovery agent N.A. Investigative [18]
15-deoxygoiazensolide DMR9SFM Discovery agent N.A. Investigative [21]
15-isobutyrylmiguanin DMQCRUG Discovery agent N.A. Investigative [21]
1beta-methoxy-miller-9Z-enolide DMHR90S Discovery agent N.A. Investigative [21]
2-amino-N-(quinolin-8-yl)benzenesulfonamide DMESFTW Discovery agent N.A. Investigative [22]
2-nitro-N-(quinolin-8-yl)benzenesulfonamide DM4Z56O Discovery agent N.A. Investigative [22]
2-oxoguaia-1,4(15), 11(13)-trien-12,8beta-olide DM3UY74 Discovery agent N.A. Investigative [21]
2-oxoguaia-1,4,11(13)-trien-12,8alpha-olide DM23WOV Discovery agent N.A. Investigative [21]
2beta-methoxy-2-deethoxyphantomolin DMWZ4KN Discovery agent N.A. Investigative [21]
3,4-epoxydehydroleucodin DM8BJPU Discovery agent N.A. Investigative [21]
4,5-ISOBUDLEIN A DMXNP2W Discovery agent N.A. Investigative [21]
4-nitro-N-(quinolin-8-yl)benzenesulfonamide DMLJDU5 Discovery agent N.A. Investigative [22]
4beta,15-epoxy-miller-9E-enolide DMDF3KJ Discovery agent N.A. Investigative [21]
4beta,15-epoxy-miller-9Z-enolide DMZ01SV Discovery agent N.A. Investigative [21]
5-bromo-N-(quinolin-8-yl)thiophene-2-sulfonamide DM37T5L Discovery agent N.A. Investigative [22]
5-chloro-N-(quinolin-8-yl)thiophene-2-sulfonamide DMMV931 Discovery agent N.A. Investigative [22]
5H-6-thia-4,5-diaza-chrysene 6,6-dioxide DM1SON5 Discovery agent N.A. Investigative [22]
7-hydroxycostunolide DMV0PT8 Discovery agent N.A. Investigative [21]
9-chloro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide DMK5DUA Discovery agent N.A. Investigative [22]
9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide DMLK0TX Discovery agent N.A. Investigative [22]
9-methyl-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide DMKD0ZP Discovery agent N.A. Investigative [22]
9alpha-acetoxy-miller-1(10)Z-enolide DMO9R6T Discovery agent N.A. Investigative [21]
ACHP DMZO5Y7 Multiple myeloma 2A83 Investigative [16]
ARTOBILOXANTHONE DMB9AR7 Discovery agent N.A. Investigative [23]
ARTORIGIDIN A DMHUXRP Discovery agent N.A. Investigative [23]
ATRIPLICIOLIDTIGLATE DML2MAI Discovery agent N.A. Investigative [18]
BAY11-7082 DMQNOFA Multiple myeloma 2A83 Investigative [16]
BUDLEIN A DMQVL2U Discovery agent N.A. Investigative [18]
Caffeic acid phenethyl ester DMRJKIV Discovery agent N.A. Investigative [24]
Centratherin DMOHELX Discovery agent N.A. Investigative [21]
DTD DMPKTB4 Discovery agent N.A. Investigative [25]
ENHYDRIN DM0STFR Discovery agent N.A. Investigative [21]
G6976 DMEZO4M Solid tumour/cancer 2A00-2F9Z Investigative [26]
Helenalin-2-methylbutyrate DMQPCDG Discovery agent N.A. Investigative [21]
HELENALINMETHACRYLATE DMPOALD Discovery agent N.A. Investigative [21]
IkappaB-alphaM DM2X3EV Discovery agent N.A. Investigative [27]
ISOGOIAZENSOLIDE DMCF1ZD Discovery agent N.A. Investigative [18]
Isohelenin DMZH9PW Discovery agent N.A. Investigative [28]
Miller-9E-enolide DM6BANS Discovery agent N.A. Investigative [21]
Miller-9Z-enolide DMFMOX5 Discovery agent N.A. Investigative [21]
MOLEPHANTIN DM4OLAZ Discovery agent N.A. Investigative [18]
MOLEPHANTININ DMGNX6M Discovery agent N.A. Investigative [18]
N-(quinolin-8-yl)thiophene-2-sulfonamide DM7O1F3 Discovery agent N.A. Investigative [22]
PS-1145 DMVUMWZ Multiple myeloma 2A83 Investigative [16]
Pycnogenol DMLFJHE Discovery agent N.A. Investigative [29]
Pyrrolidine dithiocarbamate DM5ZAS6 Discovery agent N.A. Investigative [30]
ROCAGLAMIDE DME9VTX Discovery agent N.A. Investigative [23]
SCANDENOLIDE DMX40NM Discovery agent N.A. Investigative [18]
SP-650003 DM4SXIT Discovery agent N.A. Investigative [31]
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⏷ Show the Full List of 50 Investigative Drug(s)

Molecular Expression Atlas (MEA) of This DTT

Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This DTT
Disease Name ICD 11 Studied Tissue p-value Fold-Change Z-score
Rheumatoid arthritis FA20 Synovial tissue 7.34E-09 0.84 3.94
Acute myelocytic leukaemia 2C82 Bone marrow 5.39E-01 0.16 0.27
Atopic dermatitis EA90 Skin 7.38E-10 0.54 2.85
Asthma CA23 Nasal and bronchial airway 7.89E-02 -0.2 -0.39
Multiple myeloma 2C82 Bone marrow 7.23E-01 0.02 0.08
Liver failure DD91.0 Liver tissue 3.14E-01 0.22 0.64
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⏷ Show the Full List of DTT Expression Under 6 Diseases

References

1 Emerging drugs for rheumatoid arthritis. Expert Opin Emerg Drugs. 2008 Mar;13(1):175-96.
2 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
3 Reduced astrocytic NF- B activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol. 2012 Sep;124(3):411-24.
4 Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-kappaB activation in gastric cancer cells. Oncogene. 2001 Nov 29;20(55):8009-18.
5 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
6 US patent application no. US20100278784 A1.
7 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
8 Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med. 2005 Jan 3;201(1):105-15.
9 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
10 DA-6034, a derivative of flavonoid, prevents and ameliorates dextran sulfate sodium-induced colitis and inhibits colon carcinogenesis. Exp Biol Med (Maywood). 2008 Feb;233(2):180-91.
11 Auckland Cancer Society Research Centre report
12 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800036491)
13 A water soluble parthenolide analogue suppresses in vivo tumor growth of two tobacco associated cancers, lung and bladder cancer, by targeting NF- B and generating reactive oxygen species. Int J Cancer. 2011 May 15; 128(10): 2481-2494.
14 Novel NF-B inhibitors: a patent review (2011 - 2014).Expert Opin Ther Pat. 2015 Mar;25(3):319-34.
15 Chinese herbal medicine for atopic eczema. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD002291.
16 Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
17 Gliotoxin inhibits neointimal hyperplasia after vascular injury in rats. J Vasc Res. 2009;46(4):278-89.
18 Quantitative structure-activity relationship of sesquiterpene lactones as inhibitors of the transcription factor NF-kappaB. J Med Chem. 2004 Nov 18;47(24):6042-54.
19 NF-kappaB plays a major role during the systemic and local acute inflammatory response following intestinal reperfusion injury. Br J Pharmacol. 2005 May;145(2):246-54.
20 Study of influence of additives of tyloxapol on the chromatographic characteristics of the model compounds: the comparative characterization of micellar mobile phases of tyloxapol and Triton X-100. Biomed Chromatogr. 2009 Jul;23(7):700-6.
21 Development of a structural model for NF-kappaB inhibition of sesquiterpene lactones using self-organizing neural networks. J Med Chem. 2006 Apr 6;49(7):2241-52.
22 Identification of N-(quinolin-8-yl)benzenesulfonamides as agents capable of down-regulating NFkappaB activity within two separate high-throughput s... Bioorg Med Chem Lett. 2008 Jan 1;18(1):329-35.
23 Cytotoxic and NF-kappaB inhibitory constituents of Artocarpus rigida. J Nat Prod. 2010 May 28;73(5):949-55.
24 Beneficial effects of caffeic acid phenethyl ester in a rat model of vascular injury. Br J Pharmacol. 2002 Jun;136(3):353-60.
25 A new ditriazine inhibitor of NF-kappaB modulates chronic inflammation and angiogenesis. Naunyn Schmiedebergs Arch Pharmacol. 2002 May;365(5):357-64.
26 Epidermal growth factor-induced nuclear factor kappa B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8542-7.
27 An IkappaB-alpha mutant inhibits cytokine gene expression and proliferation in human vascular smooth muscle cells. J Surg Res. 2002 Feb;102(2):198-206.
28 Protective effects of isohelenin, an inhibitor of nuclear factor kappaB, in endotoxic shock in rats. J Endotoxin Res. 2002;8(2):99-107.
29 Inhibition mechanisms of bioflavonoids extracted from the bark of Pinus maritima on the expression of proinflammatory cytokines. Ann N Y Acad Sci. 2001 Apr;928:141-56.
30 Simulated ischemia induces renal tubular cell apoptosis through a nuclear factor-kappaB dependent mechanism. J Urol. 2002 Jul;168(1):248-52.
31 Book (Current Pharmaceutical Design)