Target General Infomation
Target ID
T83145
Former ID
TTDC00046
Target Name
Nuclear factor NF-kappa-B
Gene Name
NFKB2
Synonyms
DNA-binding factor KBF2; H2TF1; Lymphocyte translocation chromosome 10; Lyt10; Nuclear factor NF-kappa-Bp52 subunit; Oncogene Lyt-10; NFKB2
Target Type
Successful
Disease Atopic dermatitis [ICD9: 691.8, 692.9; ICD10: L00-L99]
Autoimmune diabetes [ICD10: E08-E13]
Acute myeloid leukemia [ICD9: 205; ICD10: C92.0]
Asthma [ICD10: J45]
Cystic fibrosis [ICD9: 277; ICD10: E84]
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]
Multiple scierosis [ICD9: 340; ICD10: G35]
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.
Target Validation
T83145
UniProt ID
Sequence
MESCYNPGLDGIIEYDDFKLNSSIVEPKEPAPETADGPYLVIVEQPKQRGFRFRYGCEGP
SHGGLPGASSEKGRKTYPTVKICNYEGPAKIEVDLVTHSDPPRAHAHSLVGKQCSELGIC
AVSVGPKDMTAQFNNLGVLHVTKKNMMGTMIQKLQRQRLRSRPQGLTEAEQRELEQEAKE
LKKVMDLSIVRLRFSAFLRASDGSFSLPLKPVISQPIHDSKSPGASNLKISRMDKTAGSV
RGGDEVYLLCDKVQKDDIEVRFYEDDENGWQAFGDFSPTDVHKQYAIVFRTPPYHKMKIE
RPVTVFLQLKRKRGGDVSDSKQFTYYPLVEDKEEVQRKRRKALPTFSQPFGGGSHMGGGS
GGAAGGYGGAGGGGSLGFFPSSLAYSPYQSGAGPMGCYPGGGGGAQMAATVPSRDSGEEA
AEPSAPSRTPQCEPQAPEMLQRAREYNARLFGLAQRSARALLDYGVTADARALLAGQRHL
LTAQDENGDTPLHLAIIHGQTSVIEQIVYVIHHAQDLGVVNLTNHLHQTPLHLAVITGQT
SVVSFLLRVGADPALLDRHGDSAMHLALRAGAGAPELLRALLQSGAPAVPQLLHMPDFEG
LYPVHLAVRARSPECLDLLVDSGAEVEATERQGGRTALHLATEMEELGLVTHLVTKLRAN
VNARTFAGNTPLHLAAGLGYPTLTRLLLKAGADIHAENEEPLCPLPSPPTSDSDSDSEGP
EKDTRSSFRGHTPLDLTCSTKVKTLLLNAAQNTMEPPLTPPSPAGPGLSLGDTALQNLEQ
LLDGPEAQGSWAELAERLGLRSLVDTYRQTTSPSGSLLRSYELAGGDLAGLLEALSDMGL
EEGVRLLRGPETRDKLPSTAEVKEDSAYGSQSVEQEAEKLGPPPEPPGGLCHGHPQPQVH
Structure
1MDI; 1MDJ; 1MDK; 1NFI; 1SVC; 2DBF; 2O61; 3GUT; 1A3Q; 2D96; 3DO7; 4OT9
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--&gt
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 521665ClinicalTrials.gov (NCT00133341) Clinical Evaluation of the 3 Allergens: Methyldibromoglutharonitrile, Parthenolide and Goldnatriumthiosulphate. U.S. National Institutes of Health.
Ref 524716ClinicalTrials.gov (NCT02115659) Triptolide-Containing Formulation as Treatment for Autosomal Dominant Polycystic Kidney Disease (ADPKD). U.S. National Institutes of Health.
Ref 524806ClinicalTrials.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 536651Emerging drugs for rheumatoid arthritis. Expert Opin Emerg Drugs. 2008 Mar;13(1):175-96.
Ref 544147A 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 544640Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000398)
Ref 546081Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006245)
Ref 546223Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006996)
Ref 546307Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007364)
Ref 546667Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009549)
Ref 546725Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009941)
Ref 550304Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum. American Journal of Respiratory and Critical Care Medicine. 10/1996; 154(3 Pt 1):783-8.
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 527256Chinese herbal medicine for atopic eczema. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD002291.
Ref 527285J 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 527469NF-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 528110J 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 529161Bioorg 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 530845J Nat Prod. 2010 May 28;73(5):949-55.Cytotoxic and NF-kappaB inhibitory constituents of Artocarpus rigida.
Ref 535010Epidermal 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 535288N-acetylcysteine inhibited nuclear factor-kappaB expression and the intimal hyperplasia in rat carotid arterial injury. Neurol Res. 2001 Oct;23(7):731-8.
Ref 535291Role of nuclear factor-kappaB in a rat model of vascular injury. Naunyn Schmiedebergs Arch Pharmacol. 2001 Oct;364(4):343-50.
Ref 535325Functional 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 535346Inhibition 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 535347An 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 535450Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood. 2002 Jun 1;99(11):4079-86.
Ref 535453A 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 535458Beneficial effects of caffeic acid phenethyl ester in a rat model of vascular injury. Br J Pharmacol. 2002 Jun;136(3):353-60.
Ref 535461Protective effects of isohelenin, an inhibitor of nuclear factor kappaB, in endotoxic shock in rats. J Endotoxin Res. 2002;8(2):99-107.
Ref 535472Simulated ischemia induces renal tubular cell apoptosis through a nuclear factor-kappaB dependent mechanism. J Urol. 2002 Jul;168(1):248-52.
Ref 536033Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med. 2005 Jan 3;201(1):105-15.
Ref 536651Emerging drugs for rheumatoid arthritis. Expert Opin Emerg Drugs. 2008 Mar;13(1):175-96.
Ref 536946Gliotoxin inhibits neointimal hyperplasia after vascular injury in rats. J Vasc Res. 2009;46(4):278-89. Epub 2008 Nov 25.
Ref 537082Diffusion of an Ionic Drug in Micellar Aqueous Solutions. Langmuir. 2009 Feb 17.
Ref 537114Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
Ref 537170Study 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.
Ref 544147A 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 549400Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800036491)

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