Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: IL-1 receptor-associated kinase 1 (IRAK1)
• Synonyms: Interleukin-1 receptor-associated kinase 1; IRAK-1; IRAK
• Gene Name: IRAK1
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Kinase
• UniProt ID: IRAK1_HUMAN
• TTD ID: T63846
• EC Number: EC 2.7.11.1
• Sequence:
  MAGGPGPGEPAAPGAQHFLYEVPPWVMCRFYKVMDALEPADWCQFAALIVRDQTELRLCE
  RSGQRTASVLWPWINRNARVADLVHILTHLQLLRARDIITAWHPPAPLPSPGTTAPRPSS
  IPAPAEAEAWSPRKLPSSASTFLSPAFPGSQTHSGPELGLVPSPASLWPPPPSPAPSSTK
  PGPESSVSLLQGARPFPFCWPLCEISRGTHNFSEELKIGEGGFGCVYRAVMRNTVYAVKR
  LKENADLEWTAVKQSFLTEVEQLSRFRHPNIVDFAGYCAQNGFYCLVYGFLPNGSLEDRL
  HCQTQACPPLSWPQRLDILLGTARAIQFLHQDSPSLIHGDIKSSNVLLDERLTPKLGDFG
  LARFSRFAGSSPSQSSMVARTQTVRGTLAYLPEEYIKTGRLAVDTDTFSFGVVVLETLAG
  QRAVKTHGARTKYLKDLVEEEAEEAGVALRSTQSTLQAGLAADAWAAPIAMQIYKKHLDP
  RPGPCPPELGLGLGQLACCCLHRRAKRRPPMTQVYERLEKLQAVVAGVPGHSEAASCIPP
  SPQENSYVSSTGRAHSGAAPWQPLAAPSGASAQAAEQLQRGPNQPVESDESLGGLSAALR
  SWHLTPSCPLDPAPLREAGCPQGDTAGESSWGSGPGSRPTAVEGLALGSSASSSSEPPQI
  IINPARQKMVQKLALYEDGALDSLQLLSSSSLPGLGLEQDRQGPEESDEFQS
• 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. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. 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 the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3. Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  NF-kappa B signaling pathway (hsa04064)
  Toll-like receptor signaling pathway (hsa04620)
  Neurotrophin signaling pathway (hsa04722)
  Alcoholic liver disease (hsa04936)
  Pathogenic Escherichia coli infection (hsa05130)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Yersinia infection (hsa05135)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coronavirus disease - COVID-19 (hsa05171)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  MyD88 (R-HSA-166058)
  NOD1/2 Signaling Pathway (R-HSA-168638)
  p75NTR recruits signalling complexes (R-HSA-209543)
  NF-kB is activated and signals survival (R-HSA-209560)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 (R-HSA-450321)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Transcriptional Regulation by MECP2 (R-HSA-8986944)
  Interleukin-1 signaling (R-HSA-9020702)
  IRAK1 recruits IKK complex (R-HSA-937039)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  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)
  IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation (R-HSA-975144)
  MyD88 dependent cascade initiated on endosome (R-HSA-975155)
  MyD88 cascade initiated on plasma membrane (R-HSA-975871)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DTT

4 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Indazoletriazolephenyl derivative 1	DMHJDU6	N. A.	N. A.	Patented	[1]
Indazoletriazolephenyl derivative 2	DMWZLK6	N. A.	N. A.	Patented	[1]
Pyrazolopyrimidine and thienopyrimidine amide derivative 1	DM6TB4Z	N. A.	N. A.	Patented	[1]
Pyrazolopyrimidine and thienopyrimidine amide derivative 2	DMFUNH4	N. A.	N. A.	Patented	[1]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IRAK-1/4 inhibitor	DMOQBGP	Discovery agent	N.A.	Investigative	[2]
WO2012007375C1	DMOZATX	Discovery agent	N.A.	Investigative	[3]
WO2012007375C7	DMPI2MA	Discovery agent	N.A.	Investigative	[3]

References

• [1] Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015).Expert Opin Ther Pat. 2016 Aug;26(8):917-32.
• [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.
• [3] 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: 2042).