Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Inhibitor of nuclear factor kappa-B kinase alpha (IKKA)
• Synonyms: Transcription factor 16; TCF16; TCF-16; Nuclear factor NFkappaB inhibitor kinase alpha; Nuclear factor NF-kappa-B inhibitor kinase alpha; NFKBIKA; Inhibitory kappa B kinasea; Inhibitor of nuclear factor kappa-B kinase subunit alpha; IkappaB kinase A; IkBKA; IKK1; IKK-alpha; IKK-A; I-kappa-B kinase alpha; I-kappa-B kinase 1; I kappa-B kinase alpha; Conserved helix-loop-helix ubiquitous kinase
• Gene Name: CHUK
• DTT Type: Literature-reported target; [1]
• BioChemical Class: Kinase
• UniProt ID: IKKA_HUMAN
• TTD ID: T65879
• 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:
  Antifolate resistance (hsa01523)
  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)
  C-type lectin receptor signaling pathway (hsa04625)
  IL-17 signaling pathway (hsa04657)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor signaling pathway (hsa04660)
  B cell receptor signaling pathway (hsa04662)
  TNF signaling pathway (hsa04668)
  Adipocytokine signaling pathway (hsa04920)
  Alcoholic liver disease (hsa04936)
  Alzheimer disease (hsa05010)
  Epithelial cell signaling in Helicobacter pylori infection (hsa05120)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coronavirus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Pancreatic cancer (hsa05212)
  Prostate cancer (hsa05215)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Small cell lung cancer (hsa05222)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• 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

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IKI-1	DM8GQ9X	Solid tumour/cancer	2A00-2F9Z	Investigative	[1]

References

• [1] URL: 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. (Target id: 1989).