Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6Y1QZN)

• DOT Name: Interleukin-1 receptor-associated kinase-like 2 (IRAK2)
• Synonyms: IRAK-2
• Gene Name: IRAK2
• Related Disease:
  Rheumatoid arthritis
  Bacterial infection
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Hepatitis C virus infection
  Non-small-cell lung cancer
  Polycythemia vera
  Systemic lupus erythematosus
  Ulcerative colitis
  Hashimoto thyroiditis
• UniProt ID: IRAK2_HUMAN
• PDB ID: 3MOP
• Pfam ID: PF00531 ; PF00069
• Sequence:
  MACYIYQLPSWVLDDLCRNMDALSEWDWMEFASYVITDLTQLRKIKSMERVQGVSITREL
  LWWWGMRQATVQQLVDLLCRLELYRAAQIILNWKPAPEIRCPIPAFPDSVKPEKPLAASV
  RKAEDEQEEGQPVRMATFPGPGSSPARAHQPAFLQPPEEDAPHSLRSDLPTSSDSKDFST
  SIPKQEKLLSLAGDSLFWSEADVVQATDDFNQNRKISQGTFADVYRGHRHGKPFVFKKLR
  ETACSSPGSIERFFQAELQICLRCCHPNVLPVLGFCAARQFHSFIYPYMANGSLQDRLQG
  QGGSDPLPWPQRVSICSGLLCAVEYLHGLEIIHSNVKSSNVLLDQNLTPKLAHPMAHLCP
  VNKRSKYTMMKTHLLRTSAAYLPEDFIRVGQLTKRVDIFSCGIVLAEVLTGIPAMDNNRS
  PVYLKDLLLSDIPSSTASLCSRKTGVENVMAKEICQKYLEKGAGRLPEDCAEALATAACL
  CLRRRNTSLQEVCGSVAAVEERLRGRETLLPWSGLSEGTGSSSNTPEETDDVDNSSLDAS
  SSMSVAPWAGAATPLLPTENGEGRLRVIVGREADSSSEACVGLEPPQDVTETSWQIEINE
  AKRKLMENILLYKEEKVDSIELFGP
• Function: Binds to the IL-1 type I receptor following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization.
• Tissue Specificity: Expressed in spleen, thymus, prostate, lung, liver, skeletal muscle, kidney, pancreas and peripheral blood leukocytes.
• KEGG Pathway:
  Neurotrophin sig.ling pathway (hsa04722)
  Tuberculosis (hsa05152)
• Reactome Pathway:
  NOD1/2 Signaling Pathway (R-HSA-168638)
  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)
  Interleukin-1 signaling (R-HSA-9020702)
  IRAK2 mediated activation of TAK1 complex (R-HSA-937042)
  TRAF6-mediated induction of TAK1 complex within TLR4 complex (R-HSA-937072)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  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)
  IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation (R-HSA-975163)
  MyD88 cascade initiated on plasma membrane (R-HSA-975871)
  MyD88 (R-HSA-166058)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Definitive	Genetic Variation	[1]
Bacterial infection	DIS5QJ9S	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[5]
Polycythemia vera	DISB5FPO	Strong	Altered Expression	[6]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[7]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[8]
Hashimoto thyroiditis	DIS77CDF	Limited	Genetic Variation	[9]

26 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-like 2 (IRAK2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[17]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[18]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[19]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[20]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[21]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[22]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[23]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[24]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[25]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[26]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[27]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[28]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Interleukin-1 receptor-associated kinase-like 2 (IRAK2).	[19]

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-like 2 (IRAK2).	[30]

References

• [1] IRAK2 is associated with susceptibility to rheumatoid arthritis.Clin Rheumatol. 2018 Apr;37(4):927-933. doi: 10.1007/s10067-017-3906-0. Epub 2017 Nov 11.
• [2] A coding IRAK2 protein variant compromises Toll-like receptor (TLR) signaling and is associated with colorectal cancer survival.J Biol Chem. 2014 Aug 15;289(33):23123-23131. doi: 10.1074/jbc.M113.492934. Epub 2014 Jun 19.
• [3] IRAK2 counterbalances oncogenic Smurf1 in colon cancer cells by dictating ER stress.Cell Signal. 2018 Aug;48:69-80. doi: 10.1016/j.cellsig.2018.05.001. Epub 2018 May 9.
• [4] A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance.Hepatology. 2015 Nov;62(5):1375-87. doi: 10.1002/hep.28105. Epub 2015 Sep 28.
• [5] Genetic variant of IRAK2 in the toll-like receptor signaling pathway and survival of non-small cell lung cancer.Int J Cancer. 2018 Nov 15;143(10):2400-2408. doi: 10.1002/ijc.31660. Epub 2018 Sep 21.
• [6] Aberrant expression of microRNA in polycythemia vera.Haematologica. 2008 Jul;93(7):1009-16. doi: 10.3324/haematol.12706. Epub 2008 May 27.
• [7] IRAK2 is associated with systemic lupus erythematosus risk.Clin Rheumatol. 2020 Feb;39(2):419-424. doi: 10.1007/s10067-019-04781-1. Epub 2019 Oct 25.
• [8] Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis.World J Gastroenterol. 2014 Sep 14;20(34):12249-59. doi: 10.3748/wjg.v20.i34.12249.
• [9] IRAK2 and TLR10 confer risk of Hashimoto's disease: a genetic association study based on the Han Chinese population.J Hum Genet. 2019 Jul;64(7):617-623. doi: 10.1038/s10038-019-0613-5. Epub 2019 May 9.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] 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.
• [15] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [21] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [22] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [23] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [24] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [25] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [26] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [29] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [30] 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.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] 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.
• [33] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.