Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: IRAK4 messenger RNA (IRAK4 mRNA)
• Synonyms: Renal carcinoma antigenNYREN64 (mRNA); Renal carcinoma antigen NY-REN-64 (mRNA); NY-REN-64 antigen (mRNA); Interleukin1 receptorassociated kinase 4 (mRNA); Interleukin-1 receptor-associated kinase 4 (mRNA); IRAK-4 (mRNA)
• Gene Name: IRAK4
• DTT Type: Literature-reported target; [1]
• BioChemical Class: mRNA target
• UniProt ID: IRAK4_HUMAN
• TTD ID: T41766
• EC Number: EC 2.7.11.1
• Sequence:
  MNKPITPSTYVRCLNVGLIRKLSDFIDPQEGWKKLAVAIKKPSGDDRYNQFHIRRFEALL
  QTGKSPTSELLFDWGTTNCTVGDLVDLLIQNEFFAPASLLLPDAVPKTANTLPSKEAITV
  QQKQMPFCDKDRTLMTPVQNLEQSYMPPDSSSPENKSLEVSDTRFHSFSFYELKNVTNNF
  DERPISVGGNKMGEGGFGVVYKGYVNNTTVAVKKLAAMVDITTEELKQQFDQEIKVMAKC
  QHENLVELLGFSSDGDDLCLVYVYMPNGSLLDRLSCLDGTPPLSWHMRCKIAQGAANGIN
  FLHENHHIHRDIKSANILLDEAFTAKISDFGLARASEKFAQTVMTSRIVGTTAYMAPEAL
  RGEITPKSDIYSFGVVLLEIITGLPAVDEHREPQLLLDIKEEIEDEEKTIEDYIDKKMND
  ADSTSVEAMYSVASQCLHEKKNKRPDIKKVQQLLQEMTAS
• Function: Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens.
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  Apoptosis (hsa04210)
  Toll-like receptor signaling pathway (hsa04620)
  Neurotrophin signaling pathway (hsa04722)
  Pertussis (hsa05133)
  Leishmaniasis (hsa05140)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Measles (hsa05162)
  Influenza A (hsa05164)
• Reactome Pathway:
  Interleukin-1 signaling (R-HSA-446652)
  MyD88 deficiency (TLR2/4) (R-HSA-5602498)
  MyD88 deficiency (TLR5) (R-HSA-5602680)
  IRAK4 deficiency (TLR5) (R-HSA-5603037)
  IRAK4 deficiency (TLR2/4) (R-HSA-5603041)
  TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling (R-HSA-975110)
  TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (R-HSA-975138)
  MyD88 dependent cascade initiated on endosome (R-HSA-975155)
  MyD88 cascade initiated on plasma membrane (R-HSA-975871)
  MyD88 (R-HSA-166058)

Molecular Interaction Atlas (MIA) of This DTT

11 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ISIS 156449	DMPB3FH	Discovery agent	N.A.	Investigative	[1]
ISIS 156451	DMPH2W7	Discovery agent	N.A.	Investigative	[1]
ISIS 156452	DMCU6RF	Discovery agent	N.A.	Investigative	[1]
ISIS 156453	DMQ9018	Discovery agent	N.A.	Investigative	[1]
ISIS 156471	DMM9ARP	Discovery agent	N.A.	Investigative	[1]
ISIS 156472	DM3U0Z6	Discovery agent	N.A.	Investigative	[1]
ISIS 156473	DMDFUS8	Discovery agent	N.A.	Investigative	[1]
ISIS 156474	DMCXP9T	Discovery agent	N.A.	Investigative	[1]
ISIS 156475	DMNB4UJ	Discovery agent	N.A.	Investigative	[1]
N-(1H-benzo[d]imidazol-2-yl)-3-cyanobenzamide	DM054NF	Discovery agent	N.A.	Investigative	[2]
N-(1H-benzo[d]imidazol-2-yl)-3-nitrobenzamide	DM0CWPX	Discovery agent	N.A.	Investigative	[2]

References

• [1] US patent application no. 6,692,959, Antisense modulation of IL-1 receptor-associated kinase-4 expression.
• [2] Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4. Bioorg Med Chem Lett. 2006 Jun 1;16(11):2842-5.