Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0X3D17)

DOT Name Tyrosine-protein kinase JAK1 (JAK1)
Synonyms EC 2.7.10.2; Janus kinase 1; JAK-1
Gene Name JAK1
Related Disease
Autoinflammation, immune dysregulation, and eosinophilia ( )
UniProt ID
JAK1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
3EYG ; 3EYH ; 4E4L ; 4E4N ; 4E5W ; 4EHZ ; 4EI4 ; 4FK6 ; 4GS0 ; 4I5C ; 4IVB ; 4IVC ; 4IVD ; 4K6Z ; 4K77 ; 4L00 ; 4L01 ; 5E1E ; 5HX8 ; 5IXD ; 5IXI ; 5KHW ; 5KHX ; 5L04 ; 5WO4 ; 6AAH ; 6BBU ; 6C7Y ; 6DBN ; 6ELR ; 6GGH ; 6HZU ; 6N77 ; 6N78 ; 6N79 ; 6N7A ; 6N7B ; 6N7C ; 6N7D ; 6RSB ; 6RSC ; 6RSD ; 6RSE ; 6RSH ; 6SM8 ; 6SMB ; 6TPE ; 6TPF ; 6W8L ; 8EXJ
EC Number
2.7.10.2
Pfam ID
PF18379 ; PF18377 ; PF17887 ; PF07714
Sequence
MQYLNIKEDCNAMAFCAKMRSSKKTEVNLEAPEPGVEVIFYLSDREPLRLGSGEYTAEEL
CIRAAQACRISPLCHNLFALYDENTKLWYAPNRTITVDDKMSLRLHYRMRFYFTNWHGTN
DNEQSVWRHSPKKQKNGYEKKKIPDATPLLDASSLEYLFAQGQYDLVKCLAPIRDPKTEQ
DGHDIENECLGMAVLAISHYAMMKKMQLPELPKDISYKRYIPETLNKSIRQRNLLTRMRI
NNVFKDFLKEFNNKTICDSSVSTHDLKVKYLATLETLTKHYGAEIFETSMLLISSENEMN
WFHSNDGGNVLYYEVMVTGNLGIQWRHKPNVVSVEKEKNKLKRKKLENKHKKDEEKNKIR
EEWNNFSYFPEITHIVIKESVVSINKQDNKKMELKLSSHEEALSFVSLVDGYFRLTADAH
HYLCTDVAPPLIVHNIQNGCHGPICTEYAINKLRQEGSEEGMYVLRWSCTDFDNILMTVT
CFEKSEQVQGAQKQFKNFQIEVQKGRYSLHGSDRSFPSLGDLMSHLKKQILRTDNISFML
KRCCQPKPREISNLLVATKKAQEWQPVYPMSQLSFDRILKKDLVQGEHLGRGTRTHIYSG
TLMDYKDDEGTSEEKKIKVILKVLDPSHRDISLAFFEAASMMRQVSHKHIVYLYGVCVRD
VENIMVEEFVEGGPLDLFMHRKSDVLTTPWKFKVAKQLASALSYLEDKDLVHGNVCTKNL
LLAREGIDSECGPFIKLSDPGIPITVLSRQECIERIPWIAPECVEDSKNLSVAADKWSFG
TTLWEICYNGEIPLKDKTLIEKERFYESRCRPVTPSCKELADLMTRCMNYDPNQRPFFRA
IMRDINKLEEQNPDIVSEKKPATEVDPTHFEKRFLKRIRDLGEGHFGKVELCRYDPEGDN
TGEQVAVKSLKPESGGNHIADLKKEIEILRNLYHENIVKYKGICTEDGGNGIKLIMEFLP
SGSLKEYLPKNKNKINLKQQLKYAVQICKGMDYLGSRQYVHRDLAARNVLVESEHQVKIG
DFGLTKAIETDKEYYTVKDDRDSPVFWYAPECLMQSKFYIASDVWSFGVTLHELLTYCDS
DSSPMALFLKMIGPTHGQMTVTRLVNTLKEGKRLPCPPNCPDEVYQLMRKCWEFQPSNRT
SFQNLIEGFEALLK
Function
Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor as well as interleukin (IL)-10 receptor. Kinase partner for the type I interferon receptor IFNAR2. In response to interferon-binding to IFNAR1-IFNAR2 heterodimer, phosphorylates and activates its binding partner IFNAR2, creating docking sites for STAT proteins. Directly phosphorylates STAT proteins but also activates STAT signaling through the transactivation of other JAK kinases associated with signaling receptors.
Tissue Specificity Expressed at higher levels in primary colon tumors than in normal colon tissue. The expression level in metastatic colon tumors is comparable to the expression level in normal colon tissue.
KEGG Pathway
EGFR tyrosine ki.se inhibitor resistance (hsa01521 )
PI3K-Akt sig.ling pathway (hsa04151 )
Necroptosis (hsa04217 )
Osteoclast differentiation (hsa04380 )
Sig.ling pathways regulating pluripotency of stem cells (hsa04550 )
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 )
Leishmaniasis (hsa05140 )
Toxoplasmosis (hsa05145 )
Tuberculosis (hsa05152 )
Hepatitis C (hsa05160 )
Hepatitis B (hsa05161 )
Measles (hsa05162 )
Human cytomegalovirus infection (hsa05163 )
Influenza A (hsa05164 )
Human papillomavirus infection (hsa05165 )
Human T-cell leukemia virus 1 infection (hsa05166 )
Kaposi sarcoma-associated herpesvirus infection (hsa05167 )
Herpes simplex virus 1 infection (hsa05168 )
Epstein-Barr virus infection (hsa05169 )
Coro.virus disease - COVID-19 (hsa05171 )
Pathways in cancer (hsa05200 )
Viral carcinogenesis (hsa05203 )
Pancreatic cancer (hsa05212 )
PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235 )
Reactome Pathway
MAPK3 (ERK1) activation (R-HSA-110056 )
MAPK1 (ERK2) activation (R-HSA-112411 )
ISG15 antiviral mechanism (R-HSA-1169408 )
Interleukin-7 signaling (R-HSA-1266695 )
Other interleukin signaling (R-HSA-449836 )
RAF/MAP kinase cascade (R-HSA-5673001 )
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 )
Interferon gamma signaling (R-HSA-877300 )
Regulation of IFNG signaling (R-HSA-877312 )
Interleukin-20 family signaling (R-HSA-8854691 )
Interleukin-15 signaling (R-HSA-8983432 )
Interleukin-35 Signalling (R-HSA-8984722 )
Interleukin-9 signaling (R-HSA-8985947 )
Interleukin-2 signaling (R-HSA-9020558 )
Interleukin-12 signaling (R-HSA-9020591 )
Interleukin-27 signaling (R-HSA-9020956 )
Interleukin-21 signaling (R-HSA-9020958 )
Interferon alpha/beta signaling (R-HSA-909733 )
Interleukin receptor SHC signaling (R-HSA-912526 )
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 )
IFNG signaling activates MAPKs (R-HSA-9732724 )
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
Autoinflammation, immune dysregulation, and eosinophilia DISA1RWL Strong Autosomal dominant [1]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
6 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 Tyrosine-protein kinase JAK1 (JAK1). [2]
Arsenic DMTL2Y1 Approved Arsenic decreases the ubiquitination of Tyrosine-protein kinase JAK1 (JAK1). [9]
Fidarestat DMZL1I8 Phase 3 Fidarestat decreases the phosphorylation of Tyrosine-protein kinase JAK1 (JAK1). [24]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Tyrosine-protein kinase JAK1 (JAK1). [27]
EMODIN DMAEDQG Terminated EMODIN decreases the phosphorylation of Tyrosine-protein kinase JAK1 (JAK1). [32]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the methylation of Tyrosine-protein kinase JAK1 (JAK1). [33]
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⏷ Show the Full List of 6 Drug(s)
29 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 Tyrosine-protein kinase JAK1 (JAK1). [3]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Tyrosine-protein kinase JAK1 (JAK1). [4]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [5]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Tyrosine-protein kinase JAK1 (JAK1). [6]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [7]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [8]
Quercetin DM3NC4M Approved Quercetin decreases the expression of Tyrosine-protein kinase JAK1 (JAK1). [10]
Temozolomide DMKECZD Approved Temozolomide decreases the expression of Tyrosine-protein kinase JAK1 (JAK1). [11]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide decreases the expression of Tyrosine-protein kinase JAK1 (JAK1). [12]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide decreases the expression of Tyrosine-protein kinase JAK1 (JAK1). [13]
Zoledronate DMIXC7G Approved Zoledronate increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [14]
Isotretinoin DM4QTBN Approved Isotretinoin increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [15]
Bortezomib DMNO38U Approved Bortezomib decreases the expression of Tyrosine-protein kinase JAK1 (JAK1). [16]
Clozapine DMFC71L Approved Clozapine increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [17]
Tofacitinib DMBS370 Approved Tofacitinib decreases the activity of Tyrosine-protein kinase JAK1 (JAK1). [18]
Amantadine DMS3YE9 Approved Amantadine increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [19]
Interferon alfa-2B DMWCQP4 Approved Interferon alfa-2B increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [20]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [21]
Resveratrol DM3RWXL Phase 3 Resveratrol decreases the expression of Tyrosine-protein kinase JAK1 (JAK1). [22]
Tamibarotene DM3G74J Phase 3 Tamibarotene affects the expression of Tyrosine-protein kinase JAK1 (JAK1). [4]
Fenretinide DMRD5SP Phase 3 Fenretinide increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [23]
Jakafi DMNORK8 Phase 3 Jakafi decreases the activity of Tyrosine-protein kinase JAK1 (JAK1). [18]
Contigoside B DMX9V8K Phase 2/3 Contigoside B increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [25]
Beta-caryophyllene DM7583A Phase 2 Beta-caryophyllene increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [26]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [28]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [29]
PMID25656651-Compound-5 DMAI95U Patented PMID25656651-Compound-5 decreases the activity of Tyrosine-protein kinase JAK1 (JAK1). [30]
Torcetrapib DMDHYM7 Discontinued in Phase 2 Torcetrapib increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [31]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Tyrosine-protein kinase JAK1 (JAK1). [34]
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⏷ Show the Full List of 29 Drug(s)
2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
Myricetin DMTV4L0 Investigative Myricetin affects the binding of Tyrosine-protein kinase JAK1 (JAK1). [35]
Piceatannol DMYOP45 Investigative Piceatannol affects the binding of Tyrosine-protein kinase JAK1 (JAK1). [35]
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References

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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 Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
5 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.
6 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.
7 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
8 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
9 Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
10 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
11 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.
12 Arsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF-kB signaling pathways synergistically. Clin Transl Med. 2021 Feb;11(2):e335. doi: 10.1002/ctm2.335.
13 Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
14 Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
15 Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
16 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.
17 Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
18 JAK inhibitors: treatment efficacy and safety profile in patients with psoriasis. J Immunol Res. 2014;2014:283617. doi: 10.1155/2014/283617. Epub 2014 May 5.
19 Interferon signal transduction of biphenyl dimethyl dicarboxylate/amantadine and anti-HBV activity in HepG2 2.2.15. Arch Pharm Res. 2006 May;29(5):405-11. doi: 10.1007/BF02968591.
20 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.
21 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
22 Resveratrol induces apoptosis and alters gene expression in human fibrosarcoma cells. Anticancer Res. 2015 Feb;35(2):767-74.
23 Identification of retinoid-modulated proteins in squamous carcinoma cells using high-throughput immunoblotting. Cancer Res. 2004 Apr 1;64(7):2439-48. doi: 10.1158/0008-5472.can-03-2643.
24 Aldose reductase inhibition prevents metaplasia of airway epithelial cells. PLoS One. 2010 Dec 28;5(12):e14440. doi: 10.1371/journal.pone.0014440.
25 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.
26 JAK1/STAT3 regulatory effect of -caryophyllene on MG-63 osteosarcoma cells via ROS-induced apoptotic mitochondrial pathway by DNA fragmentation. J Biochem Mol Toxicol. 2020 Aug;34(8):e22514. doi: 10.1002/jbt.22514. Epub 2020 May 2.
27 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.
28 Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
29 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.
30 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.
31 Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
32 Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of STAT3. Br J Pharmacol. 2013 Oct;170(4):807-21. doi: 10.1111/bph.12302.
33 Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
34 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.
35 Myricetin directly targets JAK1 to inhibit cell transformation. Cancer Lett. 2009 Mar 8;275(1):17-26. doi: 10.1016/j.canlet.2008.09.027. Epub 2008 Nov 7.