Target Information
Target General Infomation | |||||
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Target ID |
T83145
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Former ID |
TTDC00046
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Target Name |
Nuclear factor NF-kappa-B
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Gene Name |
NFKB2
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Synonyms |
DNA-binding factor KBF2; H2TF1; Lymphocyte translocation chromosome 10; Lyt10; Nuclear factor NF-kappa-Bp52 subunit; Oncogene Lyt-10; NFKB2
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Target Type |
Successful
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Disease | Acute myeloid leukemia [ICD9: 205; ICD10: C92.0] | ||||
Asthma [ICD10: J45] | |||||
Atopic dermatitis [ICD9: 691.8, 692.9; ICD10: L00-L99] | |||||
Autoimmune diabetes [ICD10: E08-E13] | |||||
Cystic fibrosis [ICD9: 277; ICD10: E84] | |||||
Multiple scierosis [ICD9: 340; ICD10: G35] | |||||
Multiple myeloma [ICD9: 203; ICD10: C90] | |||||
Mantle cell lymphoma [ICD9: 200.4, 202.8, 203.0, 208.9; ICD10: C81-C86, C85.7, C90.0, C91-C95] | |||||
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06] | |||||
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 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.
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Target Validation |
T83145
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UniProt ID | |||||
Sequence |
MESCYNPGLDGIIEYDDFKLNSSIVEPKEPAPETADGPYLVIVEQPKQRGFRFRYGCEGP
SHGGLPGASSEKGRKTYPTVKICNYEGPAKIEVDLVTHSDPPRAHAHSLVGKQCSELGIC AVSVGPKDMTAQFNNLGVLHVTKKNMMGTMIQKLQRQRLRSRPQGLTEAEQRELEQEAKE LKKVMDLSIVRLRFSAFLRASDGSFSLPLKPVISQPIHDSKSPGASNLKISRMDKTAGSV RGGDEVYLLCDKVQKDDIEVRFYEDDENGWQAFGDFSPTDVHKQYAIVFRTPPYHKMKIE RPVTVFLQLKRKRGGDVSDSKQFTYYPLVEDKEEVQRKRRKALPTFSQPFGGGSHMGGGS GGAAGGYGGAGGGGSLGFFPSSLAYSPYQSGAGPMGCYPGGGGGAQMAATVPSRDSGEEA AEPSAPSRTPQCEPQAPEMLQRAREYNARLFGLAQRSARALLDYGVTADARALLAGQRHL LTAQDENGDTPLHLAIIHGQTSVIEQIVYVIHHAQDLGVVNLTNHLHQTPLHLAVITGQT SVVSFLLRVGADPALLDRHGDSAMHLALRAGAGAPELLRALLQSGAPAVPQLLHMPDFEG LYPVHLAVRARSPECLDLLVDSGAEVEATERQGGRTALHLATEMEELGLVTHLVTKLRAN VNARTFAGNTPLHLAAGLGYPTLTRLLLKAGADIHAENEEPLCPLPSPPTSDSDSDSEGP EKDTRSSFRGHTPLDLTCSTKVKTLLLNAAQNTMEPPLTPPSPAGPGLSLGDTALQNLEQ LLDGPEAQGSWAELAERLGLRSLVDTYRQTTSPSGSLLRSYELAGGDLAGLLEALSDMGL EEGVRLLRGPETRDKLPSTAEVKEDSAYGSQSVEQEAEKLGPPPEPPGGLCHGHPQPQVH |
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Structure |
1MDI; 1MDJ; 1MDK; 1NFI; 1SVC; 2DBF; 2O61; 3GUT; 1A3Q; 2D96; 3DO7; 4OT9
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Drugs and Mode of Action | |||||
Drug(s) | PS-341 | Drug Info | Approved | Mantle cell lymphoma | [546307], [551871] |
Sulfasalizine | Drug Info | Phase 3 | Rheumatoid arthritis | [536651] | |
Triptolide | Drug Info | Phase 3 | Autoimmune diabetes | [524716] | |
Parthenolide | Drug Info | Phase 2 | Discovery agent | [521665] | |
XP-23829 | Drug Info | Phase 2 | Multiple scierosis | [524806] | |
LC-1 | Drug Info | Phase 1 | Acute myeloid leukemia | [544147] | |
P-1 | Drug Info | Discontinued in Phase 3 | Atopic dermatitis | [546223] | |
AS602868 | Drug Info | Discontinued in Phase 1 | Multiple myeloma | [546725] | |
Gliotoxin | Drug Info | Terminated | Discovery agent | [546081] | |
HELENALIN | Drug Info | Terminated | Discovery agent | [544640] | |
MOL-218 | Drug Info | Terminated | Asthma | [546667] | |
Tyloxapol | Drug Info | Terminated | Cystic fibrosis | [550304] | |
Inhibitor | 15-ACETOXY-EREMANTHOLIDE B | Drug Info | [527285] | ||
15-DEOXYBUDLEIN A | Drug Info | [527285] | |||
15-deoxygoiazensolide | Drug Info | [528110] | |||
15-isobutyrylmiguanin | Drug Info | [528110] | |||
1beta-methoxy-miller-9Z-enolide | Drug Info | [528110] | |||
2-amino-N-(quinolin-8-yl)benzenesulfonamide | Drug Info | [529161] | |||
2-nitro-N-(quinolin-8-yl)benzenesulfonamide | Drug Info | [529161] | |||
2-oxoguaia-1,4(15), 11(13)-trien-12,8beta-olide | Drug Info | [528110] | |||
2-oxoguaia-1,4,11(13)-trien-12,8alpha-olide | Drug Info | [528110] | |||
2beta-methoxy-2-deethoxyphantomolin | Drug Info | [528110] | |||
3,4-epoxydehydroleucodin | Drug Info | [528110] | |||
4,5-ISOBUDLEIN A | Drug Info | [528110] | |||
4-nitro-N-(quinolin-8-yl)benzenesulfonamide | Drug Info | [529161] | |||
4beta,15-epoxy-miller-9E-enolide | Drug Info | [528110] | |||
4beta,15-epoxy-miller-9Z-enolide | Drug Info | [528110] | |||
5-bromo-N-(quinolin-8-yl)thiophene-2-sulfonamide | Drug Info | [529161] | |||
5-chloro-N-(quinolin-8-yl)thiophene-2-sulfonamide | Drug Info | [529161] | |||
5H-6-thia-4,5-diaza-chrysene 6,6-dioxide | Drug Info | [529161] | |||
7-hydroxycostunolide | Drug Info | [528110] | |||
9-chloro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide | Drug Info | [529161] | |||
9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide | Drug Info | [529161] | |||
9-methyl-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide | Drug Info | [529161] | |||
9alpha-acetoxy-miller-1(10)Z-enolide | Drug Info | [528110] | |||
ACHP | Drug Info | [537114] | |||
ARTOBILOXANTHONE | Drug Info | [530845] | |||
ARTORIGIDIN A | Drug Info | [530845] | |||
AS602868 | Drug Info | [537114] | |||
ATRIPLICIOLIDTIGLATE | Drug Info | [527285] | |||
BAY11-7082 | Drug Info | [537114] | |||
BUDLEIN A | Drug Info | [527285] | |||
Caffeic acid phenethyl ester | Drug Info | [535458] | |||
CENTRATHERIN | Drug Info | [528110] | |||
DTD | Drug Info | [535453] | |||
ENHYDRIN | Drug Info | [528110] | |||
Gliotoxin | Drug Info | [536946] | |||
Go6976 | Drug Info | [535010] | |||
HELENALIN | Drug Info | [527285] | |||
Helenalin-2-methylbutyrate | Drug Info | [528110] | |||
HELENALINMETHACRYLATE | Drug Info | [528110] | |||
IkappaB-alphaM | Drug Info | [535347] | |||
ISOGOIAZENSOLIDE | Drug Info | [527285] | |||
Isohelenin | Drug Info | [535461] | |||
LC-1 | Drug Info | [544147] | |||
Miller-9E-enolide | Drug Info | [528110] | |||
Miller-9Z-enolide | Drug Info | [528110] | |||
MOL-218 | Drug Info | [527469] | |||
MOLEPHANTIN | Drug Info | [527285] | |||
MOLEPHANTININ | Drug Info | [527285] | |||
N-(quinolin-8-yl)thiophene-2-sulfonamide | Drug Info | [529161] | |||
N-acetylcysteine | Drug Info | [535288] | |||
Parthenolide | Drug Info | [536033] | |||
PS-341 | Drug Info | [535450] | |||
Pycnogenol | Drug Info | [535346] | |||
Pyrrolidine dithiocarbamate | Drug Info | [535291], [535472] | |||
ROCAGLAMIDE | Drug Info | [530845] | |||
SCANDENOLIDE | Drug Info | [527285] | |||
Triptolide | Drug Info | [535325] | |||
Tyloxapol | Drug Info | [537082], [537170] | |||
XP-23829 | Drug Info | [549400] | |||
Modulator | P-1 | Drug Info | [527256] | ||
Activator | PS-1145 | Drug Info | [537114] | ||
Sulfasalizine | Drug Info | [536651] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | MAPK signaling pathway | ||||
NF-kappa B signaling pathway | |||||
Osteoclast differentiation | |||||
Legionellosis | |||||
HTLV-I infection | |||||
Epstein-Barr virus infection | |||||
Pathways in cancer | |||||
Viral carcinogenesis | |||||
NetPath Pathway | IL5 Signaling Pathway | ||||
PANTHER Pathway | Apoptosis signaling pathway | ||||
B cell activation | |||||
Inflammation mediated by chemokine and cytokine signaling pathway | |||||
T cell activation | |||||
Toll receptor signaling pathway | |||||
Pathway Interaction Database | IL12-mediated signaling events | ||||
Alternative NF-kappaB pathway | |||||
PathWhiz Pathway | Intracellular Signalling Through Adenosine Receptor A2a and Adenosine | ||||
Intracellular Signalling Through Adenosine Receptor A2b and Adenosine | |||||
Reactome | RIP-mediated NFkB activation via ZBP1 | ||||
DEx/H-box helicases activate type I IFN and inflammatory cytokines production | |||||
TAK1 activates NFkB by phosphorylation and activation of IKKs complex | |||||
Interleukin-1 processing | |||||
IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR) | |||||
IkBA variant leads to EDA-ID | |||||
Dectin-1 mediated noncanonical NF-kB signaling | |||||
NIK--> | |||||
noncanonical NF-kB signaling | |||||
TRAF6 mediated NF-kB activation | |||||
WikiPathways | Toll-like receptor signaling pathway | ||||
DNA Damage Response (only ATM dependent) | |||||
SIDS Susceptibility Pathways | |||||
Nuclear Receptors Meta-Pathway | |||||
Cytosolic sensors of pathogen-associated DNA | |||||
TAK1 activates NFkB by phosphorylation and activation of IKKs complex | |||||
EBV LMP1 signaling | |||||
TNF alpha Signaling Pathway | |||||
TSLP Signaling Pathway | |||||
Neural Crest Differentiation | |||||
TWEAK Signaling Pathway | |||||
RANKL/RANK Signaling Pathway | |||||
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways | |||||
Interleukin-1 processing | |||||
Folate Metabolism | |||||
Vitamin B12 Metabolism | |||||
Selenium Micronutrient Network | |||||
Regulation of toll-like receptor signaling pathway | |||||
References | |||||
Ref 521665 | ClinicalTrials.gov (NCT00133341) Clinical Evaluation of the 3 Allergens: Methyldibromoglutharonitrile, Parthenolide and Goldnatriumthiosulphate. U.S. National Institutes of Health. | ||||
Ref 524716 | ClinicalTrials.gov (NCT02115659) Triptolide-Containing Formulation as Treatment for Autosomal Dominant Polycystic Kidney Disease (ADPKD). U.S. National Institutes of Health. | ||||
Ref 524806 | ClinicalTrials.gov (NCT02173301) A Study to Assess the Efficacy and Safety of XP23829 in Subjects With Moderate-to-Severe Chronic Plaque-Type Psoriasis. U.S. National Institutes of Health. | ||||
Ref 544147 | 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. | ||||
Ref 544640 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000398) | ||||
Ref 546081 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006245) | ||||
Ref 546223 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006996) | ||||
Ref 546307 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007364) | ||||
Ref 546667 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009549) | ||||
Ref 546725 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009941) | ||||
Ref 527256 | Chinese herbal medicine for atopic eczema. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD002291. | ||||
Ref 527285 | J Med Chem. 2004 Nov 18;47(24):6042-54.Quantitative structure-activity relationship of sesquiterpene lactones as inhibitors of the transcription factor NF-kappaB. | ||||
Ref 527469 | 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. | ||||
Ref 528110 | J Med Chem. 2006 Apr 6;49(7):2241-52.Development of a structural model for NF-kappaB inhibition of sesquiterpene lactones using self-organizing neural networks. | ||||
Ref 529161 | Bioorg Med Chem Lett. 2008 Jan 1;18(1):329-35. Epub 2007 Oct 30.Identification of N-(quinolin-8-yl)benzenesulfonamides as agents capable of down-regulating NFkappaB activity within two separate high-throughput screens of NFkappaB activation. | ||||
Ref 530845 | J Nat Prod. 2010 May 28;73(5):949-55.Cytotoxic and NF-kappaB inhibitory constituents of Artocarpus rigida. | ||||
Ref 535010 | 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. | ||||
Ref 535288 | N-acetylcysteine inhibited nuclear factor-kappaB expression and the intimal hyperplasia in rat carotid arterial injury. Neurol Res. 2001 Oct;23(7):731-8. | ||||
Ref 535291 | Role of nuclear factor-kappaB in a rat model of vascular injury. Naunyn Schmiedebergs Arch Pharmacol. 2001 Oct;364(4):343-50. | ||||
Ref 535325 | 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. | ||||
Ref 535346 | 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. | ||||
Ref 535347 | 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. | ||||
Ref 535450 | Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood. 2002 Jun 1;99(11):4079-86. | ||||
Ref 535453 | A new ditriazine inhibitor of NF-kappaB modulates chronic inflammation and angiogenesis. Naunyn Schmiedebergs Arch Pharmacol. 2002 May;365(5):357-64. Epub 2002 Mar 19. | ||||
Ref 535458 | Beneficial effects of caffeic acid phenethyl ester in a rat model of vascular injury. Br J Pharmacol. 2002 Jun;136(3):353-60. | ||||
Ref 535461 | Protective effects of isohelenin, an inhibitor of nuclear factor kappaB, in endotoxic shock in rats. J Endotoxin Res. 2002;8(2):99-107. | ||||
Ref 535472 | Simulated ischemia induces renal tubular cell apoptosis through a nuclear factor-kappaB dependent mechanism. J Urol. 2002 Jul;168(1):248-52. | ||||
Ref 536033 | Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med. 2005 Jan 3;201(1):105-15. | ||||
Ref 536946 | Gliotoxin inhibits neointimal hyperplasia after vascular injury in rats. J Vasc Res. 2009;46(4):278-89. Epub 2008 Nov 25. | ||||
Ref 537170 | 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. |
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