Target General Infomation
Target ID
T78429
Former ID
TTDR01206
Target Name
Inhibitor of nuclear factor kappa B kinase beta subunit
Gene Name
IKBKB
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
Target Type
Clinical Trial
Disease Acne vulgaris [ICD9: 706.1; ICD10: L70.0]
Alzheimer disease [ICD9: 331; ICD10: G30]
Arthritis [ICD9: 710-719; ICD10: M00-M25]
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.
BioChemical Class
Kinase
Target Validation
T78429
UniProt ID
EC Number
EC 2.7.11.10
Sequence
MSWSPSLTTQTCGAWEMKERLGTGGFGNVIRWHNQETGEQIAIKQCRQELSPRNRERWCL
EIQIMRRLTHPNVVAARDVPEGMQNLAPNDLPLLAMEYCQGGDLRKYLNQFENCCGLREG
AILTLLSDIASALRYLHENRIIHRDLKPENIVLQQGEQRLIHKIIDLGYAKELDQGSLCT
SFVGTLQYLAPELLEQQKYTVTVDYWSFGTLAFECITGFRPFLPNWQPVQWHSKVRQKSE
VDIVVSEDLNGTVKFSSSLPYPNNLNSVLAERLEKWLQLMLMWHPRQRGTDPTYGPNGCF
KALDDILNLKLVHILNMVTGTIHTYPVTEDESLQSLKARIQQDTGIPEEDQELLQEAGLA
LIPDKPATQCISDGKLNEGHTLDMDLVFLFDNSKITYETQISPRPQPESVSCILQEPKRN
LAFFQLRKVWGQVWHSIQTLKEDCNRLQQGQRAAMMNLLRNNSCLSKMKNSMASMSQQLK
AKLDFFKTSIQIDLEKYSEQTEFGITSDKLLLAWREMEQAVELCGRENEVKLLVERMMAL
QTDIVDLQRSPMGRKQGGTLDDLEEQARELYRRLREKPRDQRTEGDSQEMVRLLLQAIQS
FEKKVRVIYTQLSKTVVCKQKALELLPKVEEVVSLMNEDEKTVVRLQEKRQKELWNLLKI
ACSKVRGPVSGSPDSMNASRLSQPGQLMSQPSTASNSLPEPAKKSEELVAEAHNLCTLLE
NAIQDTVREQDQSFTALDWSWLQTEEEEHSCLEQAS
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&amp
#xef
ve CD4+ T cells
Canonical NF-kappaB pathway
TRAIL signaling pathway
TCR signaling in na&amp
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 521620ClinicalTrials.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 521665ClinicalTrials.gov (NCT00133341) Clinical Evaluation of the 3 Allergens: Methyldibromoglutharonitrile, Parthenolide and Goldnatriumthiosulphate. U.S. National Institutes of Health.
Ref 523903ClinicalTrials.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 532068Inhibition 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 532968Activation 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 540398(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 346).
Ref 548371Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025030)
Ref 526654Bioorg Med Chem Lett. 2003 Jul 21;13(14):2419-22.Novel IKK inhibitors: beta-carbolines.
Ref 528195J 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 528764J Biol Chem. 2007 May 18;282(20):14845-52. Epub 2007 Mar 28.Cellular characterization of a novel focal adhesion kinase inhibitor.
Ref 529039Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update.
Ref 530987I?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 532068Inhibition 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 535240The 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 537968UCN-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.
Ref 544211The NF?B pathway: a therapeutic target in glioblastoma. Oncotarget. 2011 August; 2(8): 646-653.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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