Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT1F8OQ)

DTT Name IKKA messenger RNA (IKKA mRNA)
Synonyms
Transcription factor 16 (mRNA); TCF16 (mRNA); TCF-16 (mRNA); Nuclear factor NFkappaB inhibitor kinase alpha (mRNA); Nuclear factor NF-kappa-B inhibitor kinase alpha (mRNA); NFKBIKA (mRNA); Inhibitory kappa B kinasea (mRNA); Inhibitor of nuclear factor kappa-B kinase subunit alpha (mRNA); IkappaB kinase (mRNA); IkBKA (mRNA); IKK1 (mRNA); IKK-alpha (mRNA); IKK-A (mRNA); I-kappa-B kinase alpha (mRNA); I-kappa-B kinase 1 (mRNA); I kappa-B kinase alpha (mRNA); Conserved helix-loop-helix ubiquitous kinase (mRNA)
Gene Name CHUK
DTT Type
Literature-reported target
 [1]
BioChemical Class
mRNA target
UniProt ID
IKKA_HUMAN
TTD ID
T91173
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
EC 2.7.11.10
Sequence
MERPPGLRPGAGGPWEMRERLGTGGFGNVCLYQHRELDLKIAIKSCRLELSTKNRERWCH
EIQIMKKLNHANVVKACDVPEELNILIHDVPLLAMEYCSGGDLRKLLNKPENCCGLKESQ
ILSLLSDIGSGIRYLHENKIIHRDLKPENIVLQDVGGKIIHKIIDLGYAKDVDQGSLCTS
FVGTLQYLAPELFENKPYTATVDYWSFGTMVFECIAGYRPFLHHLQPFTWHEKIKKKDPK
CIFACEEMSGEVRFSSHLPQPNSLCSLVVEPMENWLQLMLNWDPQQRGGPVDLTLKQPRC
FVLMDHILNLKIVHILNMTSAKIISFLLPPDESLHSLQSRIERETGINTGSQELLSETGI
SLDPRKPASQCVLDGVRGCDSYMVYLFDKSKTVYEGPFASRSLSDCVNYIVQDSKIQLPI
IQLRKVWAEAVHYVSGLKEDYSRLFQGQRAAMLSLLRYNANLTKMKNTLISASQQLKAKL
EFFHKSIQLDLERYSEQMTYGISSEKMLKAWKEMEEKAIHYAEVGVIGYLEDQIMSLHAE
IMELQKSPYGRRQGDLMESLEQRAIDLYKQLKHRPSDHSYSDSTEMVKIIVHTVQSQDRV
LKELFGHLSKLLGCKQKIIDLLPKVEVALSNIKEADNTVMFMQGKRQKEIWHLLKIACTQ
SSARSLVGSSLEGAVTPQTSAWLPPTSAEHDHSLSCVVTPQDGETSAQMIEENLNCLGHL
STIIHEANEEQGNSMMNLDWSWLTE
Function
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 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. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor. 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.
KEGG Pathway
MAPK signaling pathway (hsa04010 )
Ras signaling pathway (hsa04014 )
Chemokine signaling pathway (hsa04062 )
NF-kappa B signaling pathway (hsa04064 )
FoxO signaling pathway (hsa04068 )
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 )
Adipocytokine signaling pathway (hsa04920 )
Epithelial cell signaling in Helicobacter pylori infection (hsa05120 )
Shigellosis (hsa05131 )
Chagas disease (American trypanosomiasis) (hsa05142 )
Toxoplasmosis (hsa05145 )
Hepatitis C (hsa05160 )
Hepatitis B (hsa05161 )
Measles (hsa05162 )
HTLV-I infection (hsa05166 )
Herpes simplex infection (hsa05168 )
Epstein-Barr virus infection (hsa05169 )
Pathways in cancer (hsa05200 )
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 )
AKT phosphorylates targets in the cytosol (R-HSA-198323 )
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 )
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 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

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
4 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
5-Bromo-6-methoxy-9H-beta-carboline DM157OQ Discovery agent N.A. Investigative [2]
ISIS 23544 DMDHY37 Discovery agent N.A. Investigative [1]
ISIS 23559 DM7NKRO Discovery agent N.A. Investigative [1]
N-(4-amino-5-cyano-6-phenylpyridin-2-yl)acetamide DMUFVM6 Discovery agent N.A. Investigative [3]
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References

1 US patent application no. 6,395,545, Antisense modulation of inhibitor-kappa B kinase-alpha expression.
2 Novel IKK inhibitors: beta-carbolines. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2419-22.
3 Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity. J Med Chem. 2006 Jun 15;49(12):3563-80.