Details of Drug Off-Target (DOT)

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

• DOT Name: Tyrosine-protein kinase Fyn (FYN)
• Synonyms: EC 2.7.10.2; Proto-oncogene Syn; Proto-oncogene c-Fyn; Src-like kinase; SLK; p59-Fyn
• Gene Name: FYN
• UniProt ID: FYN_HUMAN
• PDB ID: 1A0N ; 1AOT ; 1AOU ; 1AVZ ; 1AZG ; 1EFN ; 1FYN ; 1G83 ; 1M27 ; 1NYF ; 1NYG ; 1SHF ; 1ZBJ ; 2DQ7 ; 2MQI ; 2MRJ ; 2MRK ; 3H0F ; 3H0H ; 3H0I ; 3UA6 ; 3UA7 ; 4D8D ; 4EIK ; 4U17 ; 4U1P ; 4ZNX ; 5ZAU ; 6EDF ; 6IPY ; 6IPZ ; 7A2J ; 7A2K ; 7A2L ; 7A2M ; 7A2N ; 7A2O ; 7A2P ; 7A2Q ; 7A2R ; 7A2S ; 7A2T ; 7A2U ; 7A2V ; 7A2W ; 7A2X ; 7A2Y ; 7A2Z ; 7UD6
• EC Number: 2.7.10.2
• Pfam ID: PF07714 ; PF00017 ; PF00018
• Sequence:
  MGCVQCKDKEATKLTEERDGSLNQSSGYRYGTDPTPQHYPSFGVTSIPNYNNFHAAGGQG
  LTVFGGVNSSSHTGTLRTRGGTGVTLFVALYDYEARTEDDLSFHKGEKFQILNSSEGDWW
  EARSLTTGETGYIPSNYVAPVDSIQAEEWYFGKLGRKDAERQLLSFGNPRGTFLIRESET
  TKGAYSLSIRDWDDMKGDHVKHYKIRKLDNGGYYITTRAQFETLQQLVQHYSERAAGLCC
  RLVVPCHKGMPRLTDLSVKTKDVWEIPRESLQLIKRLGNGQFGEVWMGTWNGNTKVAIKT
  LKPGTMSPESFLEEAQIMKKLKHDKLVQLYAVVSEEPIYIVTEYMNKGSLLDFLKDGEGR
  ALKLPNLVDMAAQVAAGMAYIERMNYIHRDLRSANILVGNGLICKIADFGLARLIEDNEY
  TARQGAKFPIKWTAPEAALYGRFTIKSDVWSFGILLTELVTKGRVPYPGMNNREVLEQVE
  RGYRMPCPQDCPISLHELMIHCWKKDPEERPTFEYLQSFLEDYFTATEPQYQPGENL
• Function: Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL1 and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Phosphorylates PTK2B/PYK2 in response to T-cell receptor activation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1. In mast cells, phosphorylates CLNK after activation of immunoglobulin epsilon receptor signaling.
• Tissue Specificity: Isoform 1 is highly expressed in the brain. Isoform 2 is expressed in cells of hemopoietic lineages, especially T-lymphocytes.
• KEGG Pathway:
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  Axon guidance (hsa04360)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Platelet activation (hsa04611)
  .tural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor sig.ling pathway (hsa04660)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Cholinergic sy.pse (hsa04725)
  Prion disease (hsa05020)
  Pathogenic Escherichia coli infection (hsa05130)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  Signaling by ERBB2 (R-HSA-1227986)
  PIP3 activates AKT signaling (R-HSA-1257604)
  Signaling by SCF-KIT (R-HSA-1433557)
  Regulation of KIT signaling (R-HSA-1433559)
  Nef and signal transduction (R-HSA-164944)
  Cell surface interactions at the vascular wall (R-HSA-202733)
  FCGR activation (R-HSA-2029481)
  PECAM1 interactions (R-HSA-210990)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  DAP12 signaling (R-HSA-2424491)
  EPH-Ephrin signaling (R-HSA-2682334)
  Role of LAT2/NTAL/LAB on calcium mobilization (R-HSA-2730905)
  Nephrin family interactions (R-HSA-373753)
  NCAM signaling for neurite out-growth (R-HSA-375165)
  CD28 co-stimulation (R-HSA-389356)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  CD28 dependent Vav1 pathway (R-HSA-389359)
  CTLA4 inhibitory signaling (R-HSA-389513)
  EPHB-mediated forward signaling (R-HSA-3928662)
  EPHA-mediated growth cone collapse (R-HSA-3928663)
  Ephrin signaling (R-HSA-3928664)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Sema3A PAK dependent Axon repulsion (R-HSA-399954)
  SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion (R-HSA-399955)
  CRMPs in Sema3A signaling (R-HSA-399956)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Dectin-2 family (R-HSA-5621480)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Platelet Adhesion to exposed collagen (R-HSA-75892)
  Reelin signalling pathway (R-HSA-8866376)
  Regulation of signaling by CBL (R-HSA-912631)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants (R-HSA-9670439)
  Signaling by CSF1 (M-CSF) in myeloid cells (R-HSA-9680350)
  FLT3 signaling through SRC family kinases (R-HSA-9706374)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Tyrosine-protein kinase Fyn (FYN) affects the response to substance of Fluorouracil.	[31]
Etoposide	DMNH3PG	Approved	Tyrosine-protein kinase Fyn (FYN) affects the response to substance of Etoposide.	[31]
Mitomycin	DMH0ZJE	Approved	Tyrosine-protein kinase Fyn (FYN) affects the response to substance of Mitomycin.	[31]
Mitoxantrone	DMM39BF	Approved	Tyrosine-protein kinase Fyn (FYN) affects the response to substance of Mitoxantrone.	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Tyrosine-protein kinase Fyn (FYN).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tyrosine-protein kinase Fyn (FYN).	[8]
Ethanol	DMDRQZU	Approved	Ethanol increases the phosphorylation of Tyrosine-protein kinase Fyn (FYN).	[11]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the phosphorylation of Tyrosine-protein kinase Fyn (FYN).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tyrosine-protein kinase Fyn (FYN).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[2]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Tyrosine-protein kinase Fyn (FYN).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[10]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Tyrosine-protein kinase Fyn (FYN).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[13]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[15]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Tyrosine-protein kinase Fyn (FYN).	[16]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Tyrosine-protein kinase Fyn (FYN).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tyrosine-protein kinase Fyn (FYN).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[3]
Nabiximols	DMHKJ5I	Phase 3	Nabiximols increases the expression of Tyrosine-protein kinase Fyn (FYN).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tyrosine-protein kinase Fyn (FYN).	[24]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Tyrosine-protein kinase Fyn (FYN).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tyrosine-protein kinase Fyn (FYN).	[26]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Tyrosine-protein kinase Fyn (FYN).	[27]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Tyrosine-protein kinase Fyn (FYN).	[28]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Tyrosine-protein kinase Fyn (FYN).	[29]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid increases the activity of Tyrosine-protein kinase Fyn (FYN).	[30]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Dasatinib	DMJV2EK	Approved	Dasatinib affects the binding of Tyrosine-protein kinase Fyn (FYN).	[14]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the localization of Tyrosine-protein kinase Fyn (FYN).	[19]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [8] 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.
• [9] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [10] 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.
• [11] Positive signaling interactions between arsenic and ethanol for angiogenic gene induction in human microvascular endothelial cells. Toxicol Sci. 2008 Apr;102(2):319-27. doi: 10.1093/toxsci/kfn003. Epub 2008 Jan 8.
• [12] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood. 2008 Mar 15;111(6):3097-107.
• [15] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [16] Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2076-81. doi: 10.1073/pnas.1011936108. Epub 2011 Jan 18.
• [17] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Endocytosis of resveratrol via lipid rafts and activation of downstream signaling pathways in cancer cells. Cancer Prev Res (Phila). 2011 Jul;4(7):1095-106. doi: 10.1158/1940-6207.CAPR-10-0274. Epub 2011 Apr 5.
• [20] 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.
• [21] Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis. Eur J Neurol. 2018 Jul;25(7):934-e70. doi: 10.1111/ene.13623. Epub 2018 Apr 16.
• [22] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [23] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [28] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [29] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [30] Protein tyrosine kinase activation by polycyclic aromatic hydrocarbons in human HPB-ALL T cells. J Toxicol Environ Health A. 1999 Feb 26;56(4):249-61. doi: 10.1080/009841099158097.
• [31] 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.