Target Information

Target General Information

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Target ID

T32335 (Former ID: TTDC00222)

Target Name

Inhibitor of nuclear factor kappa-B kinase (IKK)

Synonyms

IB kinase; IkappaB kinase; IKK

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Gene Name

NO-GeName

Target Type

Patented-recorded target

[1]

Disease

[+] 2 Target-related Diseases

Multiple myeloma [ICD-11: 2A83]

Rheumatoid arthritis [ICD-11: FA20]

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.

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UniProt ID

NOUNIPROTAC

Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target Affiliated Biological Pathways		Top
Pathwhiz Pathway	[+] 2 Pathwhiz Pathways	+
1	Intracellular Signalling Through Adenosine Receptor A2a and Adenosine
2	Intracellular Signalling Through Adenosine Receptor A2b and Adenosine
Reactome	[+] 26 Reactome Pathways	+
1	Activation of NF-kappaB in B cells
2	NOD1/2 Signaling Pathway
3	RIP-mediated NFkB activation via ZBP1
4	AKT phosphorylates targets in the cytosol
5	p75NTR recruits signalling complexes
6	NF-kB is activated and signals survival
7	FCERI mediated NF-kB activation
8	Interleukin-1 signaling
9	Regulation of TNFR1 signaling
10	TNFR1-induced NFkappaB signaling pathway
11	IKBKB deficiency causes SCID
12	IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)
13	IkBA variant leads to EDA-ID
14	Dectin-1 mediated noncanonical NF-kB signaling
15	CLEC7A (Dectin-1) signaling
16	Constitutive Signaling by AKT1 E17K in Cancer
17	NIK-->noncanonical NF-kB signaling
18	MAP3K8 (TPL2)-dependent MAPK1/3 activation
19	TRAF6 mediated IRF7 activation
20	TRAF6 mediated NF-kB activation
21	NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10
22	Negative regulators of RIG-I/MDA5 signaling
23	Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon
24	IRAK1 recruits IKK complex
25	IKK complex recruitment mediated by RIP1
26	IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation
WikiPathways	[+] 43 WikiPathways	+
1	Toll-like receptor signaling pathway
2	Estrogen signaling pathway
3	TCR Signaling Pathway
4	Insulin Signaling
5	IL-4 Signaling Pathway
6	MAPK Signaling Pathway
7	NLR Proteins
8	Hair Follicle Development: Induction (Part 1 of 3)
9	MyD88 cascade initiated on plasma membrane
10	Cardiac Hypertrophic Response
11	Cytosolic sensors of pathogen-associated DNA
12	MyD88 dependent cascade initiated on endosome
13	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
14	MyD88:Mal cascade initiated on plasma membrane
15	Fc epsilon receptor (FCERI) signaling
16	MyD88-independent cascade
17	Signaling by the B Cell Receptor (BCR)
18	TAK1 activates NFkB by phosphorylation and activation of IKKs complex
19	Structural Pathway of Interleukin 1 (IL-1)
20	EBV LMP1 signaling
21	Polycystic Kidney Disease Pathway
22	Apoptosis
23	Quercetin and Nf-kB/ AP-1 Induced Cell Apoptosis
24	BDNF signaling pathway
25	Interleukin-11 Signaling Pathway
26	AGE/RAGE pathway
27	TNF alpha Signaling Pathway
28	B Cell Receptor Signaling Pathway
29	IL17 signaling pathway
30	TWEAK Signaling Pathway
31	Leptin signaling pathway
32	RANKL/RANK Signaling Pathway
33	Signalling by NGF
34	IL-1 signaling pathway
35	TCR signaling
36	RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways
37	Interleukin-1 signaling
38	Apoptosis Modulation and Signaling
39	Type II diabetes mellitus
40	MicroRNAs in cardiomyocyte hypertrophy
41	Regulation of toll-like receptor signaling pathway
42	Osteopontin Signaling
43	NOD pathway

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Novel NF-B inhibitors: a patent review (2011 - 2014).Expert Opin Ther Pat. 2015 Mar;25(3):319-34.

REF 2

IkappaB kinase, a molecular target for inhibition by 4-hydroxy-2-nonenal. J Biol Chem. 2001 May 25;276(21):18223-8.

REF 3

Novel IKK inhibitors: beta-carbolines. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2419-22.

REF 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.

REF 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.

REF 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.

REF 7

Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104.

REF 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.

REF 9

Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.

REF 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.

REF 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.

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