Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT133G8J)

• DOT Name: Interleukin-1 receptor-associated kinase 1 (IRAK1)
• Synonyms: IRAK-1; EC 2.7.11.1
• Gene Name: IRAK1
• UniProt ID: IRAK1_HUMAN
• PDB ID: 6BFN
• EC Number: 2.7.11.1
• Pfam ID: PF00531 ; PF00069
• Sequence:
  MAGGPGPGEPAAPGAQHFLYEVPPWVMCRFYKVMDALEPADWCQFAALIVRDQTELRLCE
  RSGQRTASVLWPWINRNARVADLVHILTHLQLLRARDIITAWHPPAPLPSPGTTAPRPSS
  IPAPAEAEAWSPRKLPSSASTFLSPAFPGSQTHSGPELGLVPSPASLWPPPPSPAPSSTK
  PGPESSVSLLQGARPFPFCWPLCEISRGTHNFSEELKIGEGGFGCVYRAVMRNTVYAVKR
  LKENADLEWTAVKQSFLTEVEQLSRFRHPNIVDFAGYCAQNGFYCLVYGFLPNGSLEDRL
  HCQTQACPPLSWPQRLDILLGTARAIQFLHQDSPSLIHGDIKSSNVLLDERLTPKLGDFG
  LARFSRFAGSSPSQSSMVARTQTVRGTLAYLPEEYIKTGRLAVDTDTFSFGVVVLETLAG
  QRAVKTHGARTKYLKDLVEEEAEEAGVALRSTQSTLQAGLAADAWAAPIAMQIYKKHLDP
  RPGPCPPELGLGLGQLACCCLHRRAKRRPPMTQVYERLEKLQAVVAGVPGHSEAASCIPP
  SPQENSYVSSTGRAHSGAAPWQPLAAPSGASAQAAEQLQRGPNQPVESDESLGGLSAALR
  SWHLTPSCPLDPAPLREAGCPQGDTAGESSWGSGPGSRPTAVEGLALGSSASSSSEPPQI
  IINPARQKMVQKLALYEDGALDSLQLLSSSSLPGLGLEQDRQGPEESDEFQS
• 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. 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.
• Tissue Specificity: Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  NF-kappa B sig.ling pathway (hsa04064)
  Toll-like receptor sig.ling pathway (hsa04620)
  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)
  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)
  NOD1/2 Signaling Pathway (R-HSA-168638)
  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 DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[21]

23 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 1 (IRAK1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[15]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[16]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[17]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[18]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[19]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[6]
Rutin	DMEHRAJ	Investigative	Rutin increases the expression of Interleukin-1 receptor-associated kinase 1 (IRAK1).	[24]

References

• [1] 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.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011 Jun;27(2):99-107. doi: 10.5625/lar.2011.27.2.99. Epub 2011 Jun 22.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Quercetin potentiates apoptosis by inhibiting nuclear factor-kappaB signaling in H460 lung cancer cells. Biol Pharm Bull. 2013;36(6):944-51. doi: 10.1248/bpb.b12-01004.
• [9] Characterization of arsenic trioxide resistant clones derived from Jurkat leukemia T cell line: focus on PI3K/Akt signaling pathway. Chem Biol Interact. 2013 Oct 5;205(3):198-211. doi: 10.1016/j.cbi.2013.07.011. Epub 2013 Aug 2.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [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] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [14] 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.
• [15] Comparison of gene expression in HCT116 treatment derivatives generated by two different 5-fluorouracil exposure protocols. Mol Cancer. 2004 Apr 26;3:11.
• [16] Folic acid modulates cancer-associated micro RNAs and inflammatory mediators in neoplastic and non-neoplastic colonic cells in a different way. Mol Nutr Food Res. 2017 Dec;61(12). doi: 10.1002/mnfr.201700260. Epub 2017 Nov 9.
• [17] Synergistic antiproliferative effect of arsenic trioxide combined with bortezomib in HL60 cell line and primary blasts from patients affected by myeloproliferative disorders. Cancer Genet Cytogenet. 2010 Jun;199(2):110-20. doi: 10.1016/j.cancergencyto.2010.02.010.
• [18] MiR-146a affects the alteration in myeloid differentiation induced by hydroquinone in human CD34(+) hematopoietic progenitor cells and HL-60 cells. Toxicol Res (Camb). 2016 Feb 16;5(3):848-858. doi: 10.1039/c5tx00419e. eCollection 2016 May 1.
• [19] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [20] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [21] 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.
• [22] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [24] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.