Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9JTJWC)

• DOT Name: Interleukin-1 receptor-associated kinase 4 (IRAK4)
• Synonyms: IRAK-4; EC 2.7.11.1; Renal carcinoma antigen NY-REN-64
• Gene Name: IRAK4
• Related Disease: Immunodeficiency 67
• UniProt ID: IRAK4_HUMAN
• PDB ID: 2NRU ; 2NRY ; 2O8Y ; 2OIB ; 2OIC ; 2OID ; 3MOP ; 4RMZ ; 4U97 ; 4U9A ; 4XS2 ; 4Y73 ; 4YO6 ; 4YP8 ; 4ZTL ; 4ZTM ; 4ZTN ; 5K72 ; 5K75 ; 5K76 ; 5K7G ; 5K7I ; 5KX7 ; 5KX8 ; 5T1S ; 5T1T ; 5UIQ ; 5UIR ; 5UIS ; 5UIT ; 5UIU ; 5W84 ; 5W85 ; 6EG9 ; 6EGA ; 6EGD ; 6EGE ; 6EGF ; 6F3D ; 6F3E ; 6F3G ; 6F3I ; 6LXY ; 6MOM ; 6N8G ; 6O8U ; 6O94 ; 6O95 ; 6O9D ; 6RFI ; 6RFJ ; 6THW ; 6THX ; 6THZ ; 6TI8 ; 6TIA ; 6UYA ; 6VQL ; 7C2V ; 7C2W ; 7QG1 ; 7QG2 ; 7QG3 ; 7QG5 ; 8ATB ; 8ATL ; 8ATN ; 8DKS ; 8WTF
• EC Number: 2.7.11.1
• Pfam ID: PF07714
• Sequence:
  MNKPITPSTYVRCLNVGLIRKLSDFIDPQEGWKKLAVAIKKPSGDDRYNQFHIRRFEALL
  QTGKSPTSELLFDWGTTNCTVGDLVDLLIQNEFFAPASLLLPDAVPKTANTLPSKEAITV
  QQKQMPFCDKDRTLMTPVQNLEQSYMPPDSSSPENKSLEVSDTRFHSFSFYELKNVTNNF
  DERPISVGGNKMGEGGFGVVYKGYVNNTTVAVKKLAAMVDITTEELKQQFDQEIKVMAKC
  QHENLVELLGFSSDGDDLCLVYVYMPNGSLLDRLSCLDGTPPLSWHMRCKIAQGAANGIN
  FLHENHHIHRDIKSANILLDEAFTAKISDFGLARASEKFAQTVMTSRIVGTTAYMAPEAL
  RGEITPKSDIYSFGVVLLEIITGLPAVDEHREPQLLLDIKEEIEDEEKTIEDYIDKKMND
  ADSTSVEAMYSVASQCLHEKKNKRPDIKKVQQLLQEMTAS
• Function: Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. 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.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  NF-kappa B sig.ling pathway (hsa04064)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  Neurotrophin sig.ling 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)
  Influenza A (hsa05164)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  MyD88 (R-HSA-166058)
  IRAK4 deficiency (TLR5) (R-HSA-5603037)
  IRAK4 deficiency (TLR2/4) (R-HSA-5603041)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Interleukin-1 signaling (R-HSA-9020702)
  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)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 67	DISPZ7R1	Strong	Autosomal recessive	[1]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[6]
Resiquimod	DML6XSP	Phase 2	Resiquimod increases the phosphorylation of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[13]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[8]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[9]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[10]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[11]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Interleukin-1 receptor-associated kinase 4 (IRAK4).	[14]

References

• [1] Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med. 2007 Oct 1;204(10):2407-22. doi: 10.1084/jem.20070628. Epub 2007 Sep 24.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [9] Expression and modulation of progesterone induced blocking factor (PIBF) and innate immune factors in human leukemia cell lines by progesterone and mifepristone. Leuk Lymphoma. 2007 Aug;48(8):1610-7. doi: 10.1080/10428190701471999.
• [10] Acanthoic acid protectsagainst ethanol-induced liver injury: Possible role of AMPK activation and IRAK4 inhibition. Toxicol Lett. 2017 Nov 5;281:127-138. doi: 10.1016/j.toxlet.2017.09.020. Epub 2017 Sep 28.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] IRAK4 kinase activity controls Toll-like receptor-induced inflammation through the transcription factor IRF5 in primary human monocytes. J Biol Chem. 2017 Nov 10;292(45):18689-18698. doi: 10.1074/jbc.M117.796912. Epub 2017 Sep 18.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] Nickel promotes the invasive potential of human lung cancer cells via TLR4/MyD88 signaling. Toxicology. 2011 Jul 11;285(1-2):25-30. doi: 10.1016/j.tox.2011.03.016. Epub 2011 Apr 5.