Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ8QW2L)

• DOT Name: Tyrosine-protein kinase JAK3 (JAK3)
• Synonyms: EC 2.7.10.2; Janus kinase 3; JAK-3; Leukocyte janus kinase; L-JAK
• Gene Name: JAK3
• Related Disease: T-B+ severe combined immunodeficiency due to JAK3 deficiency
• UniProt ID: JAK3_HUMAN
• PDB ID: 1YVJ ; 3LXK ; 3LXL ; 3PJC ; 3ZC6 ; 3ZEP ; 4HVD ; 4HVG ; 4HVH ; 4HVI ; 4I6Q ; 4QPS ; 4QT1 ; 4RIO ; 4V0G ; 4Z16 ; 5LWM ; 5LWN ; 5TOZ ; 5TTS ; 5TTU ; 5TTV ; 5VO6 ; 5W86 ; 5WFJ ; 6AAK ; 6DA4 ; 6DB3 ; 6DB4 ; 6DUD ; 6GL9 ; 6GLA ; 6GLB ; 6HZV ; 6NY4 ; 7APF ; 7APG ; 7C3N ; 7Q6H ; 7UYV ; 8EXM
• EC Number: 2.7.10.2
• Pfam ID: PF18379 ; PF18377 ; PF17887 ; PF07714
• Sequence:
  MAPPSEETPLIPQRSCSLLSTEAGALHVLLPARGPGPPQRLSFSFGDHLAEDLCVQAAKA
  SGILPVYHSLFALATEDLSCWFPPSHIFSVEDASTQVLLYRIRFYFPNWFGLEKCHRFGL
  RKDLASAILDLPVLEHLFAQHRSDLVSGRLPVGLSLKEQGECLSLAVLDLARMAREQAQR
  PGELLKTVSYKACLPPSLRDLIQGLSFVTRRRIRRTVRRALRRVAACQADRHSLMAKYIM
  DLERLDPAGAAETFHVGLPGALGGHDGLGLLRVAGDGGIAWTQGEQEVLQPFCDFPEIVD
  ISIKQAPRVGPAGEHRLVTVTRTDNQILEAEFPGLPEALSFVALVDGYFRLTTDSQHFFC
  KEVAPPRLLEEVAEQCHGPITLDFAINKLKTGGSRPGSYVLRRSPQDFDSFLLTVCVQNP
  LGPDYKGCLIRRSPTGTFLLVGLSRPHSSLRELLATCWDGGLHVDGVAVTLTSCCIPRPK
  EKSNLIVVQRGHSPPTSSLVQPQSQYQLSQMTFHKIPADSLEWHENLGHGSFTKIYRGCR
  HEVVDGEARKTEVLLKVMDAKHKNCMESFLEAASLMSQVSYRHLVLLHGVCMAGDSTMVQ
  EFVHLGAIDMYLRKRGHLVPASWKLQVVKQLAYALNYLEDKGLPHGNVSARKVLLAREGA
  DGSPPFIKLSDPGVSPAVLSLEMLTDRIPWVAPECLREAQTLSLEADKWGFGATVWEVFS
  GVTMPISALDPAKKLQFYEDRQQLPAPKWTELALLIQQCMAYEPVQRPSFRAVIRDLNSL
  ISSDYELLSDPTPGALAPRDGLWNGAQLYACQDPTIFEERHLKYISQLGKGNFGSVELCR
  YDPLGDNTGALVAVKQLQHSGPDQQRDFQREIQILKALHSDFIVKYRGVSYGPGRQSLRL
  VMEYLPSGCLRDFLQRHRARLDASRLLLYSSQICKGMEYLGSRRCVHRDLAARNILVESE
  AHVKIADFGLAKLLPLDKDYYVVREPGQSPIFWYAPESLSDNIFSRQSDVWSFGVVLYEL
  FTYCDKSCSPSAEFLRMMGCERDVPALCRLLELLEEGQRLPAPPACPAEVHELMKLCWAP
  SPQDRPSFSALGPQLDMLWSGSRGCETHAFTAHPEGKHHSLSFS
• Function: Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A and STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.
• Tissue Specificity: In NK cells and an NK-like cell line but not in resting T-cells or in other tissues. The S-form is more commonly seen in hematopoietic lines, whereas the B-form is detected in cells both of hematopoietic and epithelial origins.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  PI3K-Akt sig.ling pathway (hsa04151)
  Necroptosis (hsa04217)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  JAK-STAT sig.ling pathway (hsa04630)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Non-small cell lung cancer (hsa05223)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  Signaling by ALK (R-HSA-201556)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Interleukin-20 family signaling (R-HSA-8854691)
  Interleukin-15 signaling (R-HSA-8983432)
  Interleukin-9 signaling (R-HSA-8985947)
  Interleukin-2 signaling (R-HSA-9020558)
  Interleukin-21 signaling (R-HSA-9020958)
  Interleukin receptor SHC signaling (R-HSA-912526)
  Potential therapeutics for SARS (R-HSA-9679191)
  Interleukin-7 signaling (R-HSA-1266695)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
T-B+ severe combined immunodeficiency due to JAK3 deficiency	DISNT79U	Definitive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Tyrosine-protein kinase JAK3 (JAK3) decreases the response to substance of Afimoxifene.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[11]
Ceritinib	DMB920Z	Approved	Ceritinib decreases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[13]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Tyrosine-protein kinase JAK3 (JAK3).	[14]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the activity of Tyrosine-protein kinase JAK3 (JAK3).	[15]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Tyrosine-protein kinase JAK3 (JAK3).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tyrosine-protein kinase JAK3 (JAK3).	[4]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Tyrosine-protein kinase JAK3 (JAK3).	[6]
Menadione	DMSJDTY	Approved	Menadione increases the phosphorylation of Tyrosine-protein kinase JAK3 (JAK3).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tyrosine-protein kinase JAK3 (JAK3).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tyrosine-protein kinase JAK3 (JAK3).	[17]

References

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• [2] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [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] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] 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.
• [9] Tyrosine phosphorylation of HuR by JAK3 triggers dissociation and degradation of HuR target mRNAs. Nucleic Acids Res. 2014 Jan;42(2):1196-208. doi: 10.1093/nar/gkt903. Epub 2013 Oct 7.
• [10] 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.
• [11] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [12] 1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42) inhibits cell proliferation and induces apoptosis via inhibiting ALK and its downstream pathways in Karpas299 cells. Toxicol Appl Pharmacol. 2022 Sep 1;450:116156. doi: 10.1016/j.taap.2022.116156. Epub 2022 Jul 6.
• [13] 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.
• [14] EGCG enhances the therapeutic potential of gemcitabine and CP690550 by inhibiting STAT3 signaling pathway in human pancreatic cancer. PLoS One. 2012;7(2):e31067. doi: 10.1371/journal.pone.0031067. Epub 2012 Feb 13.
• [15] Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma. Leukemia. 2006 Oct;20(10):1759-66. doi: 10.1038/sj.leu.2404350. Epub 2006 Aug 17.
• [16] 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.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] 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.
• [19] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.