Details of Drug Off-Target (DOT)

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

• DOT Name: Interleukin-1 receptor-associated kinase 3 (IRAK3)
• Synonyms: IRAK-3; IL-1 receptor-associated kinase M; IRAK-M; Inactive IL-1 receptor-associated kinase 3
• Gene Name: IRAK3
• Related Disease: Asthma-related traits, susceptibility to, 5
• UniProt ID: IRAK3_HUMAN
• PDB ID: 5UKE; 6RUU; 6ZIW
• Pfam ID: PF00531 ; PF00069
• Sequence:
  MAGNCGARGALSAHTLLFDLPPALLGELCAVLDSCDGALGWRGLAERLSSSWLDVRHIEK
  YVDQGKSGTRELLWSWAQKNKTIGDLLQVLQEMGHRRAIHLITNYGAVLSPSEKSYQEGG
  FPNILFKETANVTVDNVLIPEHNEKGILLKSSISFQNIIEGTRNFHKDFLIGEGEIFEVY
  RVEIQNLTYAVKLFKQEKKMQCKKHWKRFLSELEVLLLFHHPNILELAAYFTETEKFCLI
  YPYMRNGTLFDRLQCVGDTAPLPWHIRIGILIGISKAIHYLHNVQPCSVICGSISSANIL
  LDDQFQPKLTDFAMAHFRSHLEHQSCTINMTSSSSKHLWYMPEEYIRQGKLSIKTDVYSF
  GIVIMEVLTGCRVVLDDPKHIQLRDLLRELMEKRGLDSCLSFLDKKVPPCPRNFSAKLFC
  LAGRCAATRAKLRPSMDEVLNTLESTQASLYFAEDPPTSLKSFRCPSPLFLENVPSIPVE
  DDESQNNNLLPSDEGLRIDRMTQKTPFECSQSEVMFLSLDKKPESKRNEEACNMPSSSCE
  ESWFPKYIVPSQDLRPYKVNIDPSSEAPGHSCRSRPVESSCSSKFSWDEYEQYKKE
• Function: Putative inactive protein kinase which regulates signaling downstream of immune receptors including IL1R and Toll-like receptors. Inhibits dissociation of IRAK1 and IRAK4 from the Toll-like receptor signaling complex by either inhibiting the phosphorylation of IRAK1 and IRAK4 or stabilizing the receptor complex. Upon IL33-induced lung inflammation, positively regulates expression of IL6, CSF3, CXCL2 and CCL5 mRNAs in dendritic cells.
• Tissue Specificity: Expressed in eosinophils, dendritic cells and/or monocytes (at protein level) . Expressed predominantly in peripheral blood lymphocytes .
• KEGG Pathway: Neurotrophin sig.ling pathway (hsa04722)
• Reactome Pathway:
  Interleukin-1 signaling (R-HSA-9020702)
  MyD88 (R-HSA-166058)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma-related traits, susceptibility to, 5	DISQWFCH	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Interleukin-1 receptor-associated kinase 3 (IRAK3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interleukin-1 receptor-associated kinase 3 (IRAK3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-1 receptor-associated kinase 3 (IRAK3).	[4]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Interleukin-1 receptor-associated kinase 3 (IRAK3).	[5]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Interleukin-1 receptor-associated kinase 3 (IRAK3).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-1 receptor-associated kinase 3 (IRAK3).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Interleukin-1 receptor-associated kinase 3 (IRAK3).	[2]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Interleukin-1 receptor-associated kinase 3 (IRAK3).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Interleukin-1 receptor-associated kinase 3 (IRAK3).	[7]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [6] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [7] 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.
• [8] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.