Target Information
Target General Infomation | |||||
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Target ID |
T78429
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Former ID |
TTDR01206
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Target Name |
Inhibitor of nuclear factor kappa B kinase beta subunit
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Gene Name |
IKBKB
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Synonyms |
I-kappa-B kinase 2; I-kappa-B-kinase beta; IKK-2; IKK-B; IKK-beta; IKK2; IKKbeta; IkBKB; IkappaB kinase 2; IkappaB kinase beta; Inhibitory kappa B kinase b; NFKBIKB; Nuclear factor NF-kappa-B inhibitor kinase beta; IKBKB
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Target Type |
Clinical Trial
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Disease | Arthritis [ICD9: 710-719; ICD10: M00-M25] | ||||
Acne vulgaris [ICD9: 706.1; ICD10: L70.0] | |||||
Alzheimer disease [ICD9: 331; ICD10: G30] | |||||
Osteoarthritis [ICD9: 715; ICD10: M15-M19, M47] | |||||
Function |
Serine kinase that plays an essential role in the NF- kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-Bon 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several othercomponents of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation.
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BioChemical Class |
Kinase
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Target Validation |
T78429
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UniProt ID | |||||
EC Number |
EC 2.7.11.10
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Sequence |
MSWSPSLTTQTCGAWEMKERLGTGGFGNVIRWHNQETGEQIAIKQCRQELSPRNRERWCL
EIQIMRRLTHPNVVAARDVPEGMQNLAPNDLPLLAMEYCQGGDLRKYLNQFENCCGLREG AILTLLSDIASALRYLHENRIIHRDLKPENIVLQQGEQRLIHKIIDLGYAKELDQGSLCT SFVGTLQYLAPELLEQQKYTVTVDYWSFGTLAFECITGFRPFLPNWQPVQWHSKVRQKSE VDIVVSEDLNGTVKFSSSLPYPNNLNSVLAERLEKWLQLMLMWHPRQRGTDPTYGPNGCF KALDDILNLKLVHILNMVTGTIHTYPVTEDESLQSLKARIQQDTGIPEEDQELLQEAGLA LIPDKPATQCISDGKLNEGHTLDMDLVFLFDNSKITYETQISPRPQPESVSCILQEPKRN LAFFQLRKVWGQVWHSIQTLKEDCNRLQQGQRAAMMNLLRNNSCLSKMKNSMASMSQQLK AKLDFFKTSIQIDLEKYSEQTEFGITSDKLLLAWREMEQAVELCGRENEVKLLVERMMAL QTDIVDLQRSPMGRKQGGTLDDLEEQARELYRRLREKPRDQRTEGDSQEMVRLLLQAIQS FEKKVRVIYTQLSKTVVCKQKALELLPKVEEVVSLMNEDEKTVVRLQEKRQKELWNLLKI ACSKVRGPVSGSPDSMNASRLSQPGQLMSQPSTASNSLPEPAKKSEELVAEAHNLCTLLE NAIQDTVREQDQSFTALDWSWLQTEEEEHSCLEQAS |
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Drugs and Mode of Action | |||||
Drug(s) | IMD-1041 | Drug Info | Phase 2 | Alzheimer disease | [532068] |
Parthenolide | Drug Info | Phase 2 | Discovery agent | [521665] | |
SAR-113945 | Drug Info | Phase 2 | Osteoarthritis | [523903] | |
Staurosporine | Drug Info | Phase 2 | Discovery agent | [521620], [540398] | |
IMD-0354 | Drug Info | Phase 1 | Acne vulgaris | [532968] | |
MLN0415 | Drug Info | Discontinued in Phase 1 | Arthritis | [548371] | |
Inhibitor | 2-amino-5-phenylthiophene-3-carboxamide | Drug Info | [528195] | ||
2-amino-quinoline-3-carboxylic acid amide | Drug Info | [528195] | |||
3-amino-5-(4-chlorophenyl)thiophene-2-carboxamide | Drug Info | [528195] | |||
3-amino-benzo[b]thiophene-2-carboxylic acid amide | Drug Info | [528195] | |||
4-amino-biphenyl-3-carboxylic acid amide | Drug Info | [528195] | |||
5-amino-2-p-tolyl-oxazole-4-carboxylic acid amide | Drug Info | [528195] | |||
5-amino-2-phenyl-oxazole-4-carboxylic acid amide | Drug Info | [528195] | |||
5-Bromo-6-methoxy-9H-beta-carboline | Drug Info | [526654] | |||
6-phenyl-thieno[3,2-d]pyrimidin-4-ylamine | Drug Info | [528195] | |||
IMD-0354 | Drug Info | [530987] | |||
IMD-1041 | Drug Info | [532068] | |||
Parthenolide | Drug Info | [535240] | |||
PF-228 | Drug Info | [528764] | |||
SAR-113945 | Drug Info | [544211] | |||
SC-514 | Drug Info | [529039] | |||
Staurosporine | Drug Info | [537968] | |||
Modulator | MLN0415 | Drug Info | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | MAPK signaling pathway | ||||
Ras signaling pathway | |||||
Chemokine signaling pathway | |||||
NF-kappa B signaling pathway | |||||
FoxO signaling pathway | |||||
mTOR signaling pathway | |||||
PI3K-Akt signaling pathway | |||||
Apoptosis | |||||
Osteoclast differentiation | |||||
Toll-like receptor signaling pathway | |||||
NOD-like receptor signaling pathway | |||||
RIG-I-like receptor signaling pathway | |||||
Cytosolic DNA-sensing pathway | |||||
T cell receptor signaling pathway | |||||
B cell receptor signaling pathway | |||||
TNF signaling pathway | |||||
Neurotrophin signaling pathway | |||||
Insulin signaling pathway | |||||
Adipocytokine signaling pathway | |||||
Type II diabetes mellitus | |||||
Non-alcoholic fatty liver disease (NAFLD) | |||||
Epithelial cell signaling in Helicobacter pylori infection | |||||
Shigellosis | |||||
Chagas disease (American trypanosomiasis) | |||||
Toxoplasmosis | |||||
Hepatitis C | |||||
Hepatitis B | |||||
Influenza A | |||||
HTLV-I infection | |||||
Herpes simplex infection | |||||
Epstein-Barr virus infection | |||||
Pathways in cancer | |||||
MicroRNAs in cancer | |||||
Pancreatic cancer | |||||
Prostate cancer | |||||
Chronic myeloid leukemia | |||||
Acute myeloid leukemia | |||||
Small cell lung cancer | |||||
PANTHER Pathway | Apoptosis signaling pathway | ||||
B cell activation | |||||
Inflammation mediated by chemokine and cytokine signaling pathway | |||||
Interleukin signaling pathway | |||||
PDGF signaling pathway | |||||
T cell activation | |||||
Toll receptor signaling pathway | |||||
Pathway Interaction Database | Fc-epsilon receptor I signaling in mast cells | ||||
BCR signaling pathway | |||||
GMCSF-mediated signaling events | |||||
Atypical NF-kappaB pathway | |||||
TCR signaling in na& | |||||
#xef | |||||
ve CD4+ T cells | |||||
Canonical NF-kappaB pathway | |||||
TRAIL signaling pathway | |||||
TCR signaling in na& | |||||
ve CD8+ T cells | |||||
FAS (CD95) signaling pathway | |||||
IL1-mediated signaling events | |||||
mTOR signaling pathway | |||||
TNF receptor signaling pathway | |||||
FoxO family signaling | |||||
p75(NTR)-mediated signaling | |||||
Validated transcriptional targets of TAp63 isoforms | |||||
Endogenous TLR signaling | |||||
PathWhiz Pathway | Intracellular Signalling Through Adenosine Receptor A2a and Adenosine | ||||
Intracellular Signalling Through Adenosine Receptor A2b and Adenosine | |||||
Reactome | Activation of NF-kappaB in B cells | ||||
NOD1/2 Signaling Pathway | |||||
RIP-mediated NFkB activation via ZBP1 | |||||
p75NTR recruits signalling complexes | |||||
NF-kB is activated and signals survival | |||||
FCERI mediated NF-kB activation | |||||
TAK1 activates NFkB by phosphorylation and activation of IKKs complex | |||||
Interleukin-1 signaling | |||||
Regulation of TNFR1 signaling | |||||
TNFR1-induced NFkappaB signaling pathway | |||||
IKBKB deficiency causes SCID | |||||
IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR) | |||||
IkBA variant leads to EDA-ID | |||||
CLEC7A (Dectin-1) signaling | |||||
MAP3K8 (TPL2)-dependent MAPK1/3 activation | |||||
TRAF6 mediated NF-kB activation | |||||
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 | |||||
IRAK1 recruits IKK complex | |||||
IKK complex recruitment mediated by RIP1 | |||||
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation | |||||
WikiPathways | Toll-like receptor signaling pathway | ||||
Estrogen signaling pathway | |||||
TCR Signaling Pathway | |||||
Insulin Signaling | |||||
IL-4 Signaling Pathway | |||||
MAPK Signaling Pathway | |||||
NLR Proteins | |||||
Induction (Part 1 of 3) | |||||
MyD88 cascade initiated on plasma membrane | |||||
Cardiac Hypertrophic Response | |||||
Cytosolic sensors of pathogen-associated DNA | |||||
MyD88 dependent cascade initiated on endosome | |||||
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways | |||||
Mal cascade initiated on plasma membrane | |||||
Fc epsilon receptor (FCERI) signaling | |||||
MyD88-independent cascade | |||||
Signaling by the B Cell Receptor (BCR) | |||||
TAK1 activates NFkB by phosphorylation and activation of IKKs complex | |||||
Structural Pathway of Interleukin 1 (IL-1) | |||||
EBV LMP1 signaling | |||||
Polycystic Kidney Disease Pathway | |||||
Apoptosis | |||||
Quercetin and Nf-kB/ AP-1 Induced Cell Apoptosis | |||||
BDNF signaling pathway | |||||
Interleukin-11 Signaling Pathway | |||||
AGE/RAGE pathway | |||||
TNF alpha Signaling Pathway | |||||
B Cell Receptor Signaling Pathway | |||||
IL17 signaling pathway | |||||
TWEAK Signaling Pathway | |||||
Leptin signaling pathway | |||||
RANKL/RANK Signaling Pathway | |||||
Signalling by NGF | |||||
IL-1 signaling pathway | |||||
TCR signaling | |||||
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways | |||||
Interleukin-1 signaling | |||||
Apoptosis Modulation and Signaling | |||||
Type II diabetes mellitus | |||||
MicroRNAs in cardiomyocyte hypertrophy | |||||
Regulation of toll-like receptor signaling pathway | |||||
Osteopontin Signaling | |||||
NOD pathway | |||||
References | |||||
Ref 521620 | ClinicalTrials.gov (NCT00098956) 7-hydroxystaurosporine and Topotecan Hydrochloride in Treating Patients With Relapsed or Progressed Small Cell Lung Cancer. U.S. National Institutes of Health. | ||||
Ref 521665 | ClinicalTrials.gov (NCT00133341) Clinical Evaluation of the 3 Allergens: Methyldibromoglutharonitrile, Parthenolide and Goldnatriumthiosulphate. U.S. National Institutes of Health. | ||||
Ref 523903 | ClinicalTrials.gov (NCT01598415) Safety of Single Doses of SAR113945 and Efficacy and Safety of a New Formulation Given Into the Knee in Osteoarthritis Patients / Part II. U.S. National Institutes ofHealth. | ||||
Ref 532068 | Inhibition of I?B phosphorylation prevents load-induced cardiac dysfunction in mice. Am J Physiol Heart Circ Physiol. 2012 Dec 15;303(12):H1435-45. | ||||
Ref 532968 | Activation of histamine H4 receptor inhibits TNFalpha/IMD-0354-induced apoptosis in human salivary NS-SV-AC cells. Apoptosis. 2014 Dec;19(12):1702-11. | ||||
Ref 528195 | J Med Chem. 2006 May 18;49(10):2898-908.Evolution of the thienopyridine class of inhibitors of IkappaB kinase-beta: part I: hit-to-lead strategies. | ||||
Ref 528764 | J Biol Chem. 2007 May 18;282(20):14845-52. Epub 2007 Mar 28.Cellular characterization of a novel focal adhesion kinase inhibitor. | ||||
Ref 529039 | Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update. | ||||
Ref 530987 | I?B kinase beta inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma. Clin Exp Allergy. 2011 Jan;41(1):104-15. | ||||
Ref 532068 | Inhibition of I?B phosphorylation prevents load-induced cardiac dysfunction in mice. Am J Physiol Heart Circ Physiol. 2012 Dec 15;303(12):H1435-45. | ||||
Ref 535240 | The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chem Biol. 2001 Aug;8(8):759-66. | ||||
Ref 537968 | UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Natl Cancer Inst. 1996 Jul 17;88(14):956-65. |
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