Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBY1Z5H)

• DOT Name: Dual specificity protein kinase TTK (TTK)
• Synonyms: EC 2.7.12.1; Phosphotyrosine picked threonine-protein kinase; PYT
• Gene Name: TTK
• UniProt ID: TTK_HUMAN
• PDB ID: 2X9E ; 2ZMC ; 2ZMD ; 3CEK ; 3DBQ ; 3GFW ; 3H9F ; 3HMN ; 3HMO ; 3HMP ; 3VQU ; 3W1F ; 3WYX ; 3WYY ; 3WZJ ; 3WZK ; 4B94 ; 4BHZ ; 4BI0 ; 4BI1 ; 4BI2 ; 4C4E ; 4C4F ; 4C4G ; 4C4H ; 4C4I ; 4C4J ; 4CV8 ; 4CV9 ; 4CVA ; 4D2S ; 4H7X ; 4H7Y ; 4JS8 ; 4JT3 ; 4O6L ; 4ZEG ; 5AP0 ; 5AP1 ; 5AP2 ; 5AP3 ; 5AP4 ; 5AP5 ; 5AP6 ; 5AP7 ; 5EH0 ; 5EHL ; 5EHO ; 5EHY ; 5EI2 ; 5EI6 ; 5EI8 ; 5LJJ ; 5MRB ; 5N7V ; 5N84 ; 5N87 ; 5N93 ; 5N9S ; 5NA0 ; 5NAD ; 5NTT ; 5O91 ; 6B4W ; 6GVJ ; 6H3K ; 6N6O ; 6TN9 ; 6TNB ; 6TNC ; 6TND ; 7CHM ; 7CHN ; 7CHT ; 7CIL ; 7CJA ; 7CLH ; 7LQD
• EC Number: 2.7.12.1
• Pfam ID: PF00069
• Sequence:
  MESEDLSGRELTIDSIMNKVRDIKNKFKNEDLTDELSLNKISADTTDNSGTVNQIMMMAN
  NPEDWLSLLLKLEKNSVPLSDALLNKLIGRYSQAIEALPPDKYGQNESFARIQVRFAELK
  AIQEPDDARDYFQMARANCKKFAFVHISFAQFELSQGNVKKSKQLLQKAVERGAVPLEML
  EIALRNLNLQKKQLLSEEEKKNLSASTVLTAQESFSGSLGHLQNRNNSCDSRGQTTKARF
  LYGENMPPQDAEIGYRNSLRQTNKTKQSCPFGRVPVNLLNSPDCDVKTDDSVVPCFMKRQ
  TSRSECRDLVVPGSKPSGNDSCELRNLKSVQNSHFKEPLVSDEKSSELIITDSITLKNKT
  ESSLLAKLEETKEYQEPEVPESNQKQWQSKRKSECINQNPAASSNHWQIPELARKVNTEQ
  KHTTFEQPVFSVSKQSPPISTSKWFDPKSICKTPSSNTLDDYMSCFRTPVVKNDFPPACQ
  LSTPYGQPACFQQQQHQILATPLQNLQVLASSSANECISVKGRIYSILKQIGSGGSSKVF
  QVLNEKKQIYAIKYVNLEEADNQTLDSYRNEIAYLNKLQQHSDKIIRLYDYEITDQYIYM
  VMECGNIDLNSWLKKKKSIDPWERKSYWKNMLEAVHTIHQHGIVHSDLKPANFLIVDGML
  KLIDFGIANQMQPDTTSVVKDSQVGTVNYMPPEAIKDMSSSRENGKSKSKISPKSDVWSL
  GCILYYMTYGKTPFQQIINQISKLHAIIDPNHEIEFPDIPEKDLQDVLKCCLKRDPKQRI
  SIPELLAHPYVQIQTHPVNQMAKGTTEEMKYVLGQLVGLNSPNSILKAAKTLYEHYSGGE
  SHNSSSSKTFEKKRGKK
• Function: Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Phosphorylates MAD1L1 to promote mitotic checkpoint signaling. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.
• Tissue Specificity: Present in rapidly proliferating cell lines.
• KEGG Pathway: Cell cycle (hsa04110)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Dual specificity protein kinase TTK (TTK) affects the response to substance of Doxorubicin.	[34]
Vinblastine	DM5TVS3	Approved	Dual specificity protein kinase TTK (TTK) affects the response to substance of Vinblastine.	[34]

34 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 Dual specificity protein kinase TTK (TTK).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dual specificity protein kinase TTK (TTK).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dual specificity protein kinase TTK (TTK).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dual specificity protein kinase TTK (TTK).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dual specificity protein kinase TTK (TTK).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dual specificity protein kinase TTK (TTK).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dual specificity protein kinase TTK (TTK).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Dual specificity protein kinase TTK (TTK).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Dual specificity protein kinase TTK (TTK).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Dual specificity protein kinase TTK (TTK).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Dual specificity protein kinase TTK (TTK).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Dual specificity protein kinase TTK (TTK).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Dual specificity protein kinase TTK (TTK).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Dual specificity protein kinase TTK (TTK).	[13]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Dual specificity protein kinase TTK (TTK).	[14]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Dual specificity protein kinase TTK (TTK).	[15]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Dual specificity protein kinase TTK (TTK).	[16]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Dual specificity protein kinase TTK (TTK).	[17]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Dual specificity protein kinase TTK (TTK).	[18]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Dual specificity protein kinase TTK (TTK).	[19]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Dual specificity protein kinase TTK (TTK).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Dual specificity protein kinase TTK (TTK).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Dual specificity protein kinase TTK (TTK).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dual specificity protein kinase TTK (TTK).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Dual specificity protein kinase TTK (TTK).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dual specificity protein kinase TTK (TTK).	[24]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Dual specificity protein kinase TTK (TTK).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Dual specificity protein kinase TTK (TTK).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Dual specificity protein kinase TTK (TTK).	[29]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Dual specificity protein kinase TTK (TTK).	[30]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Dual specificity protein kinase TTK (TTK).	[31]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Dual specificity protein kinase TTK (TTK).	[32]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Dual specificity protein kinase TTK (TTK).	[33]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Dual specificity protein kinase TTK (TTK).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dual specificity protein kinase TTK (TTK).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Dual specificity protein kinase TTK (TTK).	[28]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Global gene expression profiles induced by phytoestrogens in human breast cancer cells. Endocr Relat Cancer. 2008 Mar;15(1):161-73.
• [7] 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.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels. Cancer Sci. 2008 Oct;99(10):1992-2003. doi: 10.1111/j.1349-7006.2008.00955.x.
• [12] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [13] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [14] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [15] Responses of genes involved in cell cycle control to diverse DNA damaging chemicals in human lung adenocarcinoma A549 cells. Cancer Cell Int. 2005 Aug 24;5:28. doi: 10.1186/1475-2867-5-28.
• [16] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [17] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [18] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [19] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [20] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [21] Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
• [22] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [30] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [31] 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.
• [32] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [33] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [34] 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.