Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEKV1SC)

• DOT Name: Tyrosine-protein kinase FRK (FRK)
• Synonyms: EC 2.7.10.2; FYN-related kinase; Nuclear tyrosine protein kinase RAK; Protein-tyrosine kinase 5
• Gene Name: FRK
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Age-related macular degeneration
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Gout
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Advanced cancer
  Clear cell renal carcinoma
  Epstein barr virus infection
  Kidney cancer
  Renal carcinoma
  Acute myelogenous leukaemia
  Glioma
• UniProt ID: FRK_HUMAN
• EC Number: 2.7.10.2
• Pfam ID: PF07714 ; PF00017 ; PF00018
• Sequence:
  MSNICQRLWEYLEPYLPCLSTEADKSTVIENPGALCSPQSQRHGHYFVALFDYQARTAED
  LSFRAGDKLQVLDTLHEGWWFARHLEKRRDGSSQQLQGYIPSNYVAEDRSLQAEPWFFGA
  IGRSDAEKQLLYSENKTGSFLIRESESQKGEFSLSVLDGAVVKHYRIKRLDEGGFFLTRR
  RIFSTLNEFVSHYTKTSDGLCVKLGKPCLKIQVPAPFDLSYKTVDQWEIDRNSIQLLKRL
  GSGQFGEVWEGLWNNTTPVAVKTLKPGSMDPNDFLREAQIMKNLRHPKLIQLYAVCTLED
  PIYIITELMRHGSLQEYLQNDTGSKIHLTQQVDMAAQVASGMAYLESRNYIHRDLAARNV
  LVGEHNIYKVADFGLARVFKVDNEDIYESRHEIKLPVKWTAPEAIRSNKFSIKSDVWSFG
  ILLYEIITYGKMPYSGMTGAQVIQMLAQNYRLPQPSNCPQQFYNIMLECWNAEPKERPTF
  ETLRWKLEDYFETDSSYSDANNFIR
• Function: Non-receptor tyrosine-protein kinase that negatively regulates cell proliferation. Positively regulates PTEN protein stability through phosphorylation of PTEN on 'Tyr-336', which in turn prevents its ubiquitination and degradation, possibly by reducing its binding to NEDD4. May function as a tumor suppressor.
• Tissue Specificity: Predominantly expressed in epithelial derived cell lines and tissues, especially normal liver, kidney, breast and colon.
• Reactome Pathway:
  Regulation of PTEN stability and activity (R-HSA-8948751)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Genetic Variation	[1]
Prostate carcinoma	DISMJPLE	Definitive	Genetic Variation	[1]
Age-related macular degeneration	DIS0XS2C	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[6]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[6]
Gout	DISHC0U7	Strong	Genetic Variation	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[11]
Epstein barr virus infection	DISOO0WT	moderate	Altered Expression	[12]
Kidney cancer	DISBIPKM	moderate	Biomarker	[11]
Renal carcinoma	DISER9XT	moderate	Biomarker	[11]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[13]
Glioma	DIS5RPEH	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
NAPQI	DM8F5LR	Investigative	Tyrosine-protein kinase FRK (FRK) affects the response to substance of NAPQI.	[35]

19 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 Tyrosine-protein kinase FRK (FRK).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tyrosine-protein kinase FRK (FRK).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tyrosine-protein kinase FRK (FRK).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tyrosine-protein kinase FRK (FRK).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tyrosine-protein kinase FRK (FRK).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tyrosine-protein kinase FRK (FRK).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tyrosine-protein kinase FRK (FRK).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tyrosine-protein kinase FRK (FRK).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tyrosine-protein kinase FRK (FRK).	[22]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tyrosine-protein kinase FRK (FRK).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tyrosine-protein kinase FRK (FRK).	[25]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Tyrosine-protein kinase FRK (FRK).	[26]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Tyrosine-protein kinase FRK (FRK).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tyrosine-protein kinase FRK (FRK).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Tyrosine-protein kinase FRK (FRK).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tyrosine-protein kinase FRK (FRK).	[31]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Tyrosine-protein kinase FRK (FRK).	[33]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Tyrosine-protein kinase FRK (FRK).	[21]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Tyrosine-protein kinase FRK (FRK).	[34]

1 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 FRK (FRK).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the phosphorylation of Tyrosine-protein kinase FRK (FRK).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Tyrosine-protein kinase FRK (FRK).	[32]

References

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• [2] Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration.Hum Mol Genet. 2011 Sep 15;20(18):3699-709. doi: 10.1093/hmg/ddr270. Epub 2011 Jun 10.
• [3] No genetic association between Fyn kinase gene polymorphisms (-93A/G, IVS10+37T/C and Ex12+894T/G) and Japanese sporadic Alzheimer's disease.Neurosci Lett. 2004 Apr 22;360(1-2):109-11. doi: 10.1016/j.neulet.2004.02.046.
• [4] Repression of Fyn-related kinase in breast cancer cells is associated with promoter site-specific CpG methylation.Oncotarget. 2017 Feb 14;8(7):11442-11459. doi: 10.18632/oncotarget.14546.
• [5] Breast cancer cell line proliferation blocked by the Src-related Rak tyrosine kinase.Int J Cancer. 2003 Mar 20;104(2):139-46. doi: 10.1002/ijc.10925.
• [6] Fyn-related kinase expression predicts favorable prognosis in patients with cervical cancer and suppresses malignant progression by regulating migration and invasion.Biomed Pharmacother. 2016 Dec;84:270-276. doi: 10.1016/j.biopha.2016.09.042. Epub 2016 Sep 22.
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• [10] Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth.J Neurooncol. 2019 May;143(1):35-47. doi: 10.1007/s11060-019-03143-w. Epub 2019 Apr 16.
• [11] miR-19 promotes the proliferation of clear cell renal cell carcinoma by targeting the FRK-PTEN axis.Onco Targets Ther. 2019 Apr 10;12:2713-2727. doi: 10.2147/OTT.S199238. eCollection 2019.
• [12] Epstein-barr virus gene expression, human leukocyte antigen alleles and chronic high viral loads in pediatric renal transplant patients.Transplantation. 2011 Aug 15;92(3):328-33. doi: 10.1097/TP.0b013e3182247bf2.
• [13] Identification of a SRC-like tyrosine kinase gene, FRK, fused with ETV6 in a patient with acute myelogenous leukemia carrying a t(6;12)(q21;p13) translocation.Genes Chromosomes Cancer. 2005 Mar;42(3):269-79. doi: 10.1002/gcc.20147.
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• [17] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [21] 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.
• [22] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [23] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [24] The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood. 2008 Mar 15;111(6):3097-107.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [27] 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.
• [28] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [29] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [30] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [35] Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011 Mar;120(1):33-41. doi: 10.1093/toxsci/kfq375. Epub 2010 Dec 22.