Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Inhibitor of nuclear factor kappa-B kinase (IKK)
• Synonyms: IB kinase; IkappaB kinase; IKK
• Gene Name: IKK
• DTT Type: Patented-recorded target; [1]
• UniProt ID: NOUNIPROTAC
• TTD ID: T32335
• 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-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 sincethey 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.
• Reactome Pathway:
  NOD1/2 Signaling Pathway (R-HSA-168638)
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)
  AKT phosphorylates targets in the cytosol (R-HSA-198323)
  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)
  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)
  Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  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)
  Negative regulators of RIG-I/MDA5 signaling (R-HSA-936440)
  Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon (R-HSA-936964)
  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

4 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dihydrothieno [2,3-e]indazole derivative 1	DMUJ3XK	N. A.	N. A.	Patented	[1]
Dihydrothieno [2,3-e]indazole derivative 2	DM0D3HU	N. A.	N. A.	Patented	[1]
Dihydrothieno [2,3-e]indazole derivative 3	DM85VQR	N. A.	N. A.	Patented	[1]
Dihydrothieno [2,3-e]indazole derivative 4	DMR4LPO	N. A.	N. A.	Patented	[1]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-hydroxy-2-nonenal	DM2LJFZ	Discovery agent	N.A.	Investigative	[2]
5-Bromo-6-methoxy-9H-beta-carboline	DM157OQ	Discovery agent	N.A.	Investigative	[3]
Arsenite	DMBCO4Q	Discovery agent	N.A.	Investigative	[4]
BMS-345541	DM7D519	Arthritis	FA20	Investigative	[5]
MLN-120B	DMYKNSP	Discovery agent	N.A.	Investigative	[6]
MRT67307	DMYRCHG	Discovery agent	N.A.	Investigative	[7]
PMID23099093C17d	DMWS7O9	Discovery agent	N.A.	Investigative	[8]
PS-1145	DMVUMWZ	Multiple myeloma	2A83	Investigative	[9]
S1627	DMD4KLQ	Discovery agent	N.A.	Investigative	[10]
TPCA-1	DMA14PR	Discovery agent	N.A.	Investigative	[11]

References

• [1] Novel NF-B inhibitors: a patent review (2011 - 2014).Expert Opin Ther Pat. 2015 Mar;25(3):319-34.
• [2] IkappaB kinase, a molecular target for inhibition by 4-hydroxy-2-nonenal. J Biol Chem. 2001 May 25;276(21):18223-8.
• [3] Novel IKK inhibitors: beta-carbolines. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2419-22.
• [4] Inhibition of NF-kappa B activation by arsenite through reaction with a critical cysteine in the activation loop of Ikappa B kinase. J Biol Chem. 2000 Nov 17;275(46):36062-6.
• [5] A highly selective inhibitor of I kappa B kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum. 2003 Sep;48(9):2652-9.
• [6] A selective small molecule IkappaB Kinase beta inhibitor blocks nuclear factor kappaB-mediated inflammatory responses in human fibroblast-like syno... J Pharmacol Exp Ther. 2006 Jun;317(3):989-1001.
• [7] Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104.
• [8] Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKepsilon kinases. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7169-73.
• [9] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [10] Specific Inhibition of IkappaB kinase reduces hyperalgesia in inflammatory and neuropathic pain models in rats. J Neurosci. 2004 Feb 18;24(7):1637-45.
• [11] Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB Kinase 2, TPCA-1 (2-[(aminocarbo... J Pharmacol Exp Ther. 2005 Jan;312(1):373-81.