Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTJ3E9X)

• DTT Name: Inhibitor of nuclear factor kappa-B kinase beta (IKKB)
• Synonyms: Nuclear factor NF-kappa-B inhibitor kinase beta; NFKBIKB; Inhibitor of nuclear factor kappa-B kinase subunit beta; IkBKB; IKKB; IKK2; IKK-beta; IKK-B; I-kappa-B-kinase beta; I-kappa-B kinase 2
• Gene Name: IKBKB
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: IKKB_HUMAN
• TTD ID: T78429
• EC Number: EC 2.7.11.10
• Sequence:
  MSWSPSLTTQTCGAWEMKERLGTGGFGNVIRWHNQETGEQIAIKQCRQELSPRNRERWCL
  EIQIMRRLTHPNVVAARDVPEGMQNLAPNDLPLLAMEYCQGGDLRKYLNQFENCCGLREG
  AILTLLSDIASALRYLHENRIIHRDLKPENIVLQQGEQRLIHKIIDLGYAKELDQGSLCT
  SFVGTLQYLAPELLEQQKYTVTVDYWSFGTLAFECITGFRPFLPNWQPVQWHSKVRQKSE
  VDIVVSEDLNGTVKFSSSLPYPNNLNSVLAERLEKWLQLMLMWHPRQRGTDPTYGPNGCF
  KALDDILNLKLVHILNMVTGTIHTYPVTEDESLQSLKARIQQDTGIPEEDQELLQEAGLA
  LIPDKPATQCISDGKLNEGHTLDMDLVFLFDNSKITYETQISPRPQPESVSCILQEPKRN
  LAFFQLRKVWGQVWHSIQTLKEDCNRLQQGQRAAMMNLLRNNSCLSKMKNSMASMSQQLK
  AKLDFFKTSIQIDLEKYSEQTEFGITSDKLLLAWREMEQAVELCGRENEVKLLVERMMAL
  QTDIVDLQRSPMGRKQGGTLDDLEEQARELYRRLREKPRDQRTEGDSQEMVRLLLQAIQS
  FEKKVRVIYTQLSKTVVCKQKALELLPKVEEVVSLMNEDEKTVVRLQEKRQKELWNLLKI
  ACSKVRGPVSGSPDSMNASRLSQPGQLMSQPSTASNSLPEPAKKSEELVAEAHNLCTLLE
  NAIQDTVREQDQSFTALDWSWLQTEEEEHSCLEQAS
• 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. Phosphorylates inhibitors of NF-kappa-B on 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 other components 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. Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor. 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.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Ras signaling pathway (hsa04014)
  Chemokine signaling pathway (hsa04062)
  NF-kappa B signaling pathway (hsa04064)
  FoxO signaling pathway (hsa04068)
  mTOR signaling pathway (hsa04150)
  PI3K-Akt signaling pathway (hsa04151)
  Apoptosis (hsa04210)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor signaling pathway (hsa04620)
  NOD-like receptor signaling pathway (hsa04621)
  RIG-I-like receptor signaling pathway (hsa04622)
  Cytosolic DNA-sensing pathway (hsa04623)
  T cell receptor signaling pathway (hsa04660)
  B cell receptor signaling pathway (hsa04662)
  TNF signaling pathway (hsa04668)
  Neurotrophin signaling pathway (hsa04722)
  Insulin signaling pathway (hsa04910)
  Adipocytokine signaling pathway (hsa04920)
  Type II diabetes mellitus (hsa04930)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Epithelial cell signaling in Helicobacter pylori infection (hsa05120)
  Shigellosis (hsa05131)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Influenza A (hsa05164)
  HTLV-I infection (hsa05166)
  Herpes simplex infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  MicroRNAs in cancer (hsa05206)
  Pancreatic cancer (hsa05212)
  Prostate cancer (hsa05215)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  NOD1/2 Signaling Pathway (R-HSA-168638)
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)
  p75NTR recruits signalling complexes (R-HSA-209543)
  NF-kB is activated and signals survival (R-HSA-209560)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  TAK1 activates NFkB by phosphorylation and activation of IKKs complex (R-HSA-445989)
  Interleukin-1 signaling (R-HSA-446652)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NFkappaB signaling pathway (R-HSA-5357956)
  IKBKB deficiency causes SCID (R-HSA-5602636)
  IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR) (R-HSA-5603027)
  IkBA variant leads to EDA-ID (R-HSA-5603029)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 (R-HSA-933543)
  IRAK1 recruits IKK complex (R-HSA-937039)
  IKK complex recruitment mediated by RIP1 (R-HSA-937041)
  IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation (R-HSA-975144)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Arsenic trioxide	DM61TA4	Acute lymphoblastic leukaemia	2A85	Approved	[2]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IMD-1041	DMU1MR9	Alzheimer disease	8A20	Phase 2	[3]
Parthenolide	DMCQBFT	N. A.	N. A.	Phase 2	[4]
SAR-113945	DMMCA9V	Osteoarthritis	FA00-FA05	Phase 2	[1]
IMD-0354	DMOFSLE	Acne vulgaris	ED80	Phase 1	[5]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MLN0415	DMG72VK	Arthritis	FA20	Discontinued in Phase 1	[6]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-amino-5-phenylthiophene-3-carboxamide	DMOQ2R8	Discovery agent	N.A.	Investigative	[7]
2-amino-quinoline-3-carboxylic acid amide	DME4856	Discovery agent	N.A.	Investigative	[7]
3-amino-5-(4-chlorophenyl)thiophene-2-carboxamide	DM2U9RY	Discovery agent	N.A.	Investigative	[7]
3-amino-benzo[b]thiophene-2-carboxylic acid amide	DMWOTD3	Discovery agent	N.A.	Investigative	[7]
4-amino-biphenyl-3-carboxylic acid amide	DMHDB70	Discovery agent	N.A.	Investigative	[7]
5-amino-2-p-tolyl-oxazole-4-carboxylic acid amide	DM4SWJ7	Discovery agent	N.A.	Investigative	[7]
5-amino-2-phenyl-oxazole-4-carboxylic acid amide	DMX37ZC	Discovery agent	N.A.	Investigative	[7]
5-Bromo-6-methoxy-9H-beta-carboline	DM157OQ	Discovery agent	N.A.	Investigative	[8]
6-phenyl-thieno[3,2-d]pyrimidin-4-ylamine	DME230I	Discovery agent	N.A.	Investigative	[7]
PF-228	DM32FKD	Discovery agent	N.A.	Investigative	[9]
SC-514	DMAWI4M	Discovery agent	N.A.	Investigative	[10]
Staurosporine	DM0E9BR	Discovery agent	N.A.	Investigative	[11]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Osteoarthritis	FA20	Synovial tissue	5.64E-01	0.07	0.17
Alzheimer's disease	8A00.0	Entorhinal cortex	5.74E-08	0.26	0.88
Rheumatoid arthritis	FA20	Synovial tissue	1.28E-03	1.27	2.63

References

• [1] The NF B pathway: a therapeutic target in glioblastoma. Oncotarget. 2011 August; 2(8): 646-653.
• [2] How acute promyelocytic leukaemia revived arsenic. Nat Rev Cancer. 2002 Sep;2(9):705-13.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Company report (Millennium)
• [7] Evolution of the thienopyridine class of inhibitors of IkappaB kinase-beta: part I: hit-to-lead strategies. J Med Chem. 2006 May 18;49(10):2898-908.
• [8] Novel IKK inhibitors: beta-carbolines. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2419-22.
• [9] Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007 May 18;282(20):14845-52.
• [10] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.
• [11] 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.