Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ09CG8)

• DOT Name: Serine/threonine-protein kinase tousled-like 2 (TLK2)
• Synonyms: EC 2.7.11.1; HsHPK; PKU-alpha; Tousled-like kinase 2
• Gene Name: TLK2
• Related Disease:
  Intellectual disability, autosomal dominant 57
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Intellectual disability
  Isolated congenital microcephaly
  Neoplasm
  Neurodevelopmental disorder
  West syndrome
  Encephalitis
  Lung neoplasm
  Neuroblastoma
  Neurofibromatosis type 1
  Prostate cancer
  Prostate carcinoma
  Autism spectrum disorder
• UniProt ID: TLK2_HUMAN
• PDB ID: 5O0Y; 7LO0
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MMEELHSLDPRRQELLEARFTGVGVSKGPLNSESSNQSLCSVGSLSDKEVETPEKKQNDQ
  RNRKRKAEPYETSQGKGTPRGHKISDYFEFAGGSAPGTSPGRSVPPVARSSPQHSLSNPL
  PRRVEQPLYGLDGSAAKEATEEQSALPTLMSVMLAKPRLDTEQLAQRGAGLCFTFVSAQQ
  NSPSSTGSGNTEHSCSSQKQISIQHRQTQSDLTIEKISALENSKNSDLEKKEGRIDDLLR
  ANCDLRRQIDEQQKMLEKYKERLNRCVTMSKKLLIEKSKQEKMACRDKSMQDRLRLGHFT
  TVRHGASFTEQWTDGYAFQNLIKQQERINSQREEIERQRKMLAKRKPPAMGQAPPATNEQ
  KQRKSKTNGAENETPSSGNTELKDTAPALGAHSLLRLTLAEYHEQEEIFKLRLGHLKKEE
  AEIQAELERLERVRNLHIRELKRIHNEDNSQFKDHPTLNDRYLLLHLLGRGGFSEVYKAF
  DLTEQRYVAVKIHQLNKNWRDEKKENYHKHACREYRIHKELDHPRIVKLYDYFSLDTDSF
  CTVLEYCEGNDLDFYLKQHKLMSEKEARSIIMQIVNALKYLNEIKPPIIHYDLKPGNILL
  VNGTACGEIKITDFGLSKIMDDDSYNSVDGMELTSQGAGTYWYLPPECFVVGKEPPKISN
  KVDVWSVGVIFYQCLYGRKPFGHNQSQQDILQENTILKATEVQFPPKPVVTPEAKAFIRR
  CLAYRKEDRIDVQQLACDPYLLPHIRKSVSTSSPAGAAIASTSGASNNSSSN
• Function: Serine/threonine-protein kinase involved in the process of chromatin assembly and probably also DNA replication, transcription, repair, and chromosome segregation. Phosphorylates the chromatin assembly factors ASF1A and ASF1B. Phosphorylation of ASF1A prevents its proteasome-mediated degradation, thereby enhancing chromatin assembly. Negative regulator of amino acid starvation-induced autophagy.
• Tissue Specificity: Detected in placenta, fetal liver, kidney, pancreas, heart and skeletal muscle . Highly expressed in testis . Detected in spleen, thymus, colon, ovary, small intestine, prostate and peripheral blood leukocytes . Almost undetectable in liver and lung .

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 57	DISEF521	Definitive	Autosomal dominant	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[6]
West syndrome	DISLIAU9	Strong	Genetic Variation	[7]
Encephalitis	DISLD1RL	moderate	Biomarker	[8]
Lung neoplasm	DISVARNB	moderate	Biomarker	[8]
Neuroblastoma	DISVZBI4	moderate	Genetic Variation	[9]
Neurofibromatosis type 1	DIS53JH9	moderate	Biomarker	[9]
Prostate cancer	DISF190Y	moderate	Biomarker	[10]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[10]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Serine/threonine-protein kinase tousled-like 2 (TLK2).	[22]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] TLK2 enhances aggressive phenotypes of glioblastoma cells through the activation of SRC signaling pathway.Cancer Biol Ther. 2019;20(1):101-108. doi: 10.1080/15384047.2018.1507257. Epub 2018 Sep 12.
• [3] Amplification of TLK2 Induces Genomic Instability via Impairing the G2-M Checkpoint.Mol Cancer Res. 2016 Oct;14(10):920-927. doi: 10.1158/1541-7786.MCR-16-0161. Epub 2016 Aug 3.
• [4] Comprehensive functional analysis of the tousled-like kinase 2 frequently amplified in aggressive luminal breast cancers.Nat Commun. 2016 Oct 3;7:12991. doi: 10.1038/ncomms12991.
• [5] From mosquito to man: identification of a novel protein kinase, HsHPK, which is highly expressed in human hepatoma tissues.J Biomed Sci. 1998;5(2):135-40. doi: 10.1007/BF02258367.
• [6] The Tousled-like kinases regulate genome and epigenome stability: implications in development and disease.Cell Mol Life Sci. 2019 Oct;76(19):3827-3841. doi: 10.1007/s00018-019-03208-z. Epub 2019 Jul 13.
• [7] Severe neurodevelopmental disease caused by a homozygous TLK2 variant.Eur J Hum Genet. 2020 Mar;28(3):383-387. doi: 10.1038/s41431-019-0519-x.
• [8] Chemoproteomic Discovery of a Ritanserin-Targeted Kinase Network Mediating Apoptotic Cell Death of Lung Tumor Cells.Mol Pharmacol. 2018 Nov;94(5):1246-1255. doi: 10.1124/mol.118.113001. Epub 2018 Aug 29.
• [9] Localization of the 17q breakpoint of a constitutional 1;17 translocation in a patient with neuroblastoma within a 25-kb segment located between the ACCN1 and TLK2 genes and near the distal breakpoints of two microdeletions in neurofibromatosis type 1 patients.Genes Chromosomes Cancer. 2002 Oct;35(2):113-20. doi: 10.1002/gcc.10034.
• [10] The expression of Tousled kinases in CaP cell lines and its relation to radiation response and DSB repair.Prostate. 2011 Sep 15;71(13):1367-73. doi: 10.1002/pros.21358. Epub 2011 Feb 14.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Phosphoproteomics reveals resveratrol-dependent inhibition of Akt/mTORC1/S6K1 signaling. J Proteome Res. 2014 Dec 5;13(12):5734-42. doi: 10.1021/pr500714a. Epub 2014 Oct 29.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] 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.
• [21] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.