Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHEOTA8)

• DOT Name: Non-receptor tyrosine-protein kinase TYK2
• Synonyms: EC 2.7.10.2
• Gene Name: TYK2
• Related Disease: Immunodeficiency 35
• UniProt ID: TYK2_HUMAN
• PDB ID: 3LXN ; 3LXP ; 3NYX ; 3NZ0 ; 3ZON ; 4GFO ; 4GIH ; 4GII ; 4GJ2 ; 4GJ3 ; 4GVJ ; 4OLI ; 4PO6 ; 4PY1 ; 4WOV ; 5C01 ; 5C03 ; 5F1Z ; 5F20 ; 5TKD ; 5WAL ; 6AAM ; 6DBK ; 6DBM ; 6NSL ; 6NZE ; 6NZF ; 6NZH ; 6NZP ; 6NZQ ; 6NZR ; 6OVA ; 6VNS ; 6VNV ; 6VNX ; 6VNY ; 6X8F ; 6X8G ; 7AX4 ; 7K7O ; 7K7Q ; 7UYR ; 7UYS ; 7UYT ; 7UYU ; 8EXN ; 8EYC ; 8S98 ; 8S99 ; 8S9A ; 8TB5 ; 8TB6
• EC Number: 2.7.10.2
• Pfam ID: PF18379 ; PF18377 ; PF17887 ; PF07714
• Sequence:
  MPLRHWGMARGSKPVGDGAQPMAAMGGLKVLLHWAGPGGGEPWVTFSESSLTAEEVCIHI
  AHKVGITPPCFNLFALFDAQAQVWLPPNHILEIPRDASLMLYFRIRFYFRNWHGMNPREP
  AVYRCGPPGTEASSDQTAQGMQLLDPASFEYLFEQGKHEFVNDVASLWELSTEEEIHHFK
  NESLGMAFLHLCHLALRHGIPLEEVAKKTSFKDCIPRSFRRHIRQHSALTRLRLRNVFRR
  FLRDFQPGRLSQQMVMVKYLATLERLAPRFGTERVPVCHLRLLAQAEGEPCYIRDSGVAP
  TDPGPESAAGPPTHEVLVTGTGGIQWWPVEEEVNKEEGSSGSSGRNPQASLFGKKAKAHK
  AVGQPADRPREPLWAYFCDFRDITHVVLKEHCVSIHRQDNKCLELSLPSRAAALSFVSLV
  DGYFRLTADSSHYLCHEVAPPRLVMSIRDGIHGPLLEPFVQAKLRPEDGLYLIHWSTSHP
  YRLILTVAQRSQAPDGMQSLRLRKFPIEQQDGAFVLEGWGRSFPSVRELGAALQGCLLRA
  GDDCFSLRRCCLPQPGETSNLIIMRGARASPRTLNLSQLSFHRVDQKEITQLSHLGQGTR
  TNVYEGRLRVEGSGDPEEGKMDDEDPLVPGRDRGQELRVVLKVLDPSHHDIALAFYETAS
  LMSQVSHTHLAFVHGVCVRGPENIMVTEYVEHGPLDVWLRRERGHVPMAWKMVVAQQLAS
  ALSYLENKNLVHGNVCGRNILLARLGLAEGTSPFIKLSDPGVGLGALSREERVERIPWLA
  PECLPGGANSLSTAMDKWGFGATLLEICFDGEAPLQSRSPSEKEHFYQRQHRLPEPSCPQ
  LATLTSQCLTYEPTQRPSFRTILRDLTRLQPHNLADVLTVNPDSPASDPTVFHKRYLKKI
  RDLGEGHFGKVSLYCYDPTNDGTGEMVAVKALKADCGPQHRSGWKQEIDILRTLYHEHII
  KYKGCCEDQGEKSLQLVMEYVPLGSLRDYLPRHSIGLAQLLLFAQQICEGMAYLHAQHYI
  HRDLAARNVLLDNDRLVKIGDFGLAKAVPEGHEYYRVREDGDSPVFWYAPECLKEYKFYY
  ASDVWSFGVTLYELLTHCDSSQSPPTKFLELIGIAQGQMTVLRLTELLERGERLPRPDKC
  PCEVYHLMKNCWETEASFRPTFENLIPILKTVHEKYQGQAPSVFSVC
• Function: Tyrosine kinase of the non-receptor type involved in numerous cytokines and interferons signaling, which regulates cell growth, development, cell migration, innate and adaptive immunity. Plays both structural and catalytic roles in numerous interleukins and interferons (IFN-alpha/beta) signaling. Associates with heterodimeric cytokine receptor complexes and activates STAT family members including STAT1, STAT3, STAT4 or STAT6. The heterodimeric cytokine receptor complexes are composed of (1) a TYK2-associated receptor chain (IFNAR1, IL12RB1, IL10RB or IL13RA1), and (2) a second receptor chain associated either with JAK1 or JAK2. In response to cytokine-binding to receptors, phosphorylates and activates receptors (IFNAR1, IL12RB1, IL10RB or IL13RA1), creating docking sites for STAT members. In turn, recruited STATs are phosphorylated by TYK2 (or JAK1/JAK2 on the second receptor chain), form homo- and heterodimers, translocate to the nucleus, and regulate cytokine/growth factor responsive genes. Negatively regulates STAT3 activity by promototing phosphorylation at a specific tyrosine that differs from the site used for signaling.
• Tissue Specificity: Observed in all cell lines analyzed. Expressed in a variety of lymphoid and non-lymphoid cell lines.
• KEGG Pathway:
  Necroptosis (hsa04217)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  JAK-STAT sig.ling pathway (hsa04630)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  Toxoplasmosis (hsa05145)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  MAPK3 (ERK1) activation (R-HSA-110056)
  MAPK1 (ERK2) activation (R-HSA-112411)
  Other interleukin signaling (R-HSA-449836)
  Interleukin-10 signaling (R-HSA-6783783)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  IL-6-type cytokine receptor ligand interactions (R-HSA-6788467)
  Interleukin-20 family signaling (R-HSA-8854691)
  Interleukin-35 Signalling (R-HSA-8984722)
  Interleukin-12 signaling (R-HSA-9020591)
  Interleukin-23 signaling (R-HSA-9020933)
  Interleukin-27 signaling (R-HSA-9020956)
  Interferon alpha/beta signaling (R-HSA-909733)
  Regulation of IFNA/IFNB signaling (R-HSA-912694)
  Signaling by CSF3 (G-CSF) (R-HSA-9674555)
  Potential therapeutics for SARS (R-HSA-9679191)
  Inactivation of CSF3 (G-CSF) signaling (R-HSA-9705462)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Interleukin-6 signaling (R-HSA-1059683)

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 35	DIS7LW0D	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Non-receptor tyrosine-protein kinase TYK2 affects the response to substance of Methotrexate.	[17]
Cocaine	DMSOX7I	Approved	Non-receptor tyrosine-protein kinase TYK2 affects the response to substance of Cocaine.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Non-receptor tyrosine-protein kinase TYK2.	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Non-receptor tyrosine-protein kinase TYK2.	[3]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Non-receptor tyrosine-protein kinase TYK2.	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Non-receptor tyrosine-protein kinase TYK2.	[5]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Non-receptor tyrosine-protein kinase TYK2.	[5]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Non-receptor tyrosine-protein kinase TYK2.	[6]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Non-receptor tyrosine-protein kinase TYK2.	[7]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Non-receptor tyrosine-protein kinase TYK2.	[8]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Non-receptor tyrosine-protein kinase TYK2.	[9]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Non-receptor tyrosine-protein kinase TYK2.	[10]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Non-receptor tyrosine-protein kinase TYK2.	[11]
Interferon alfa-2B	DMWCQP4	Approved	Interferon alfa-2B increases the expression of Non-receptor tyrosine-protein kinase TYK2.	[12]
Contigoside B	DMX9V8K	Phase 2/3	Contigoside B affects the expression of Non-receptor tyrosine-protein kinase TYK2.	[10]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Non-receptor tyrosine-protein kinase TYK2.	[14]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of Non-receptor tyrosine-protein kinase TYK2.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the phosphorylation of Non-receptor tyrosine-protein kinase TYK2.	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Non-receptor tyrosine-protein kinase TYK2.	[15]

References

• [1] Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity. 2000 Oct;13(4):549-60. doi: 10.1016/s1074-7613(00)00054-6.
• [2] 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.
• [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] 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.
• [5] [Effect of arsenic trioxide and 5-aza-2'-deoxycytidine on SHP-1, JAK3, TYK2 gene expression in K562 cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Apr;22(2):323-8. doi: 10.7534/j.issn.1009-2137.2014.02.011.
• [6] 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.
• [7] Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways. Int J Mol Sci. 2019 Nov 30;20(23):6039. doi: 10.3390/ijms20236039.
• [8] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [9] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [10] Improved Preventive Effects of Combined Bioactive Compounds Present in Different Blueberry Varieties as Compared to Single Phytochemicals. Nutrients. 2018 Dec 29;11(1):61. doi: 10.3390/nu11010061.
• [11] 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.
• [12] 6-Hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside potentiates the anti-proliferative effect of interferon / by promoting activation of the JAK/STAT signaling by inhibiting SOCS3 in hepatocellular carcinoma cells. Toxicol Appl Pharmacol. 2017 Dec 1;336:31-39. doi: 10.1016/j.taap.2017.10.004. Epub 2017 Oct 12.
• [13] Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome. Sci Rep. 2014 Dec 4;4:7310. doi: 10.1038/srep07310.
• [14] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [18] Substance dependence low-density whole genome association study in two distinct American populations. Hum Genet. 2008 Jun;123(5):495-506. doi: 10.1007/s00439-008-0501-0. Epub 2008 Apr 26.