Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTICTXI8)

• DOT Name: Serine/threonine-protein kinase tousled-like 1 (TLK1)
• Synonyms: EC 2.7.11.1; PKU-beta; Tousled-like kinase 1
• Gene Name: TLK1
• Related Disease:
  B-cell neoplasm
  Melanoma
  Thyroid gland papillary carcinoma
  Advanced cancer
  Bladder cancer
  Breast neoplasm
  Cholangiocarcinoma
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Non-small-cell lung cancer
  Tuberculosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Ductal breast carcinoma in situ
  Osteoarthritis
  Pancreatic cancer
  Breast cancer
  Breast carcinoma
  Cutaneous melanoma
  Autism spectrum disorder
  Female hypogonadism
  Intellectual disability
  Isolated congenital microcephaly
  Neoplasm
  Neurodevelopmental disorder
  Pneumonia
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
• UniProt ID: TLK1_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MSVQSSSGSLEGPPSWSQLSTSPTPGSAAAARSLLNHTPPSGRPREGAMDELHSLDPRRQ
  ELLEARFTGVASGSTGSTGSCSVGAKASTNNESSNHSFGSLGSLSDKESETPEKKQSESS
  RGRKRKAENQNESSQGKSIGGRGHKISDYFEYQGGNGSSPVRGIPPAIRSPQNSHSHSTP
  SSSVRPNSPSPTALAFGDHPIVQPKQLSFKIIQTDLTMLKLAALESNKIQDLEKKEGRID
  DLLRANCDLRRQIDEQQKLLEKYKERLNKCISMSKKLLIEKSTQEKLSSREKSMQDRLRL
  GHFTTVRHGASFTEQWTDGFAFQNLVKQQEWVNQQREDIERQRKLLAKRKPPTANNSQAP
  STNSEPKQRKNKAVNGAENDPFVRPNLPQLLTLAEYHEQEEIFKLRLGHLKKEEAEIQAE
  LERLERVRNLHIRELKRINNEDNSQFKDHPTLNERYLLLHLLGRGGFSEVYKAFDLYEQR
  YAAVKIHQLNKSWRDEKKENYHKHACREYRIHKELDHPRIVKLYDYFSLDTDTFCTVLEY
  CEGNDLDFYLKQHKLMSEKEARSIVMQIVNALRYLNEIKPPIIHYDLKPGNILLVDGTAC
  GEIKITDFGLSKIMDDDSYGVDGMDLTSQGAGTYWYLPPECFVVGKEPPKISNKVDVWSV
  GVIFFQCLYGRKPFGHNQSQQDILQENTILKATEVQFPVKPVVSSEAKAFIRRCLAYRKE
  DRFDVHQLANDPYLLPHMRRSNSSGNLHMAGLTASPTPPSSSIITY
• Function: Rapidly and transiently inhibited by phosphorylation following the generation of DNA double-stranded breaks during S-phase. This is cell cycle checkpoint and ATM-pathway dependent and appears to regulate processes involved in chromatin assembly. Isoform 3 phosphorylates and enhances the stability of the t-SNARE SNAP23, augmenting its assembly with syntaxin. Isoform 3 protects the cells from the ionizing radiation by facilitating the repair of DSBs. In vitro, phosphorylates histone H3 at 'Ser-10'.
• Tissue Specificity: Widely expressed. Present in fetal placenta, liver, kidney and pancreas but not heart or skeletal muscle. Also found in adult cell lines. Isoform 3 is ubiquitously expressed in all tissues examined.

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Altered Expression	[1]
Melanoma	DIS1RRCY	Definitive	Biomarker	[2]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[8]
Glioma	DIS5RPEH	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[9]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[10]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[5]
Ductal breast carcinoma in situ	DISLCJY7	moderate	Biomarker	[11]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[12]
Pancreatic cancer	DISJC981	moderate	Biomarker	[13]
Breast cancer	DIS7DPX1	Disputed	Altered Expression	[14]
Breast carcinoma	DIS2UE88	Disputed	Altered Expression	[14]
Cutaneous melanoma	DIS3MMH9	Disputed	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Limited	Biomarker	[15]
Female hypogonadism	DISWASB4	Limited	Biomarker	[16]
Intellectual disability	DISMBNXP	Limited	Altered Expression	[15]
Isolated congenital microcephaly	DISUXHZ6	Limited	Biomarker	[15]
Neoplasm	DISZKGEW	Limited	Biomarker	[17]
Neurodevelopmental disorder	DIS372XH	Limited	Altered Expression	[15]
Pneumonia	DIS8EF3M	Limited	Genetic Variation	[18]
Prostate cancer	DISF190Y	Limited	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[19]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[17]

10 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 Serine/threonine-protein kinase tousled-like 1 (TLK1).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[23]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[20]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein kinase tousled-like 1 (TLK1).	[27]

References

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• [7] Silencing of Tousled-like kinase 1 sensitizes cholangiocarcinoma cells to cisplatin-induced apoptosis.Cancer Lett. 2010 Oct 1;296(1):27-34. doi: 10.1016/j.canlet.2010.03.011. Epub 2010 Apr 9.
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• [9] Drug resistance to targeted therapeutic strategies in non-small cell lung cancer.Pharmacol Ther. 2020 Feb;206:107438. doi: 10.1016/j.pharmthera.2019.107438. Epub 2019 Nov 9.
• [10] Synthesis and antimycobacterial activity of imidazo[1,2-b][1,2,4,5]tetrazines.Eur J Med Chem. 2019 Sep 15;178:39-47. doi: 10.1016/j.ejmech.2019.05.081. Epub 2019 May 31.
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• [13] Primate-specific miRNA-637 inhibited tumorigenesis in human pancreatic ductal adenocarcinoma cells by suppressing Akt1 expression.Exp Cell Res. 2018 Feb 15;363(2):310-314. doi: 10.1016/j.yexcr.2018.01.026.
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• [17] Loss of miR-16 contributes to tumor progression by activation of tousled-like kinase 1 in oral squamous cell carcinoma.Cell Cycle. 2018;17(18):2284-2295. doi: 10.1080/15384101.2018.1526601. Epub 2018 Oct 9.
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• [19] Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors.Int J Cancer. 2019 Aug 15;145(4):1055-1067. doi: 10.1002/ijc.32200. Epub 2019 Feb 25.
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• [22] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [23] 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.
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• [27] 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.
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