Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXG5RWQ)

• DOT Name: Non-receptor tyrosine-protein kinase TNK1 (TNK1)
• Synonyms: EC 2.7.10.2; CD38 negative kinase 1
• Gene Name: TNK1
• UniProt ID: TNK1_HUMAN
• PDB ID: 7T8J; 7TCY; 7TDY; 7U4W; 7U4Z
• EC Number: 2.7.10.2
• Pfam ID: PF07714
• Sequence:
  MLPEAGSLWLLKLLRDIQLAQFYWPILEELNVTRPEHFDFVKPEDLDGIGMGRPAQRRLS
  EALKRLRSGPKSKNWVYKILGGFAPEHKEPTLPSDSPRHLPEPEGGLKCLIPEGAVCRGE
  LLGSGCFGVVHRGLWTLPSGKSVPVAVKSLRVGPEGPMGTELGDFLREVSVMMNLEHPHV
  LRLHGLVLGQPLQMVMELAPLGSLHARLTAPAPTPPLLVALLCLFLRQLAGAMAYLGARG
  LVHRDLATRNLLLASPRTIKVADFGLVRPLGGARGRYVMGGPRPIPYAWCAPESLRHGAF
  SSASDVWMFGVTLWEMFSGGEEPWAGVPPYLILQRLEDRARLPRPPLCSRALYSLALRCW
  APHPADRPSFSHLEGLLQEAGPSEACCVRDVTEPGALRMETGDPITVIEGSSSFHSPDST
  IWKGQNGRTFKVGSFPASAVTLADAGGLPATRPVHRGTPARGDQHPGSIDGDRKKANLWD
  APPARGQRRNMPLERMKGISRSLESVLSLGPRPTGGGSSPPEIRQARAVPQGPPGLPPRP
  PLSSSSPQPSQPSRERLPWPKRKPPHNHPMGMPGARKAAALSGGLLSDPELQRKIMEVEL
  SVHGVTHQECQTALGATGGDVVSAIRNLKVDQLFHLSSRSRADCWRILEHYQWDLSAASR
  YVLARP
• Function: Involved in negative regulation of cell growth. Has tumor suppressor properties. Plays a negative regulatory role in the Ras-MAPK pathway. May function in signaling pathways utilized broadly during fetal development and more selectively in adult tissues and in cells of the lymphohematopoietic system. Could specifically be involved in phospholipid signal transduction.
• Tissue Specificity: Expressed in all umbilical cord blood, bone marrow and adult blood cell sub-populations and in several leukemia cell lines. Highly expressed in fetal blood, brain, lung, liver and kidney. Detected at lower levels in adult prostate, testis, ovary, small intestine and colon. Not expressed in adult lung, liver, kidney or brain.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Non-receptor tyrosine-protein kinase TNK1 (TNK1) decreases the response to substance of Arsenic trioxide.	[9]

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 Non-receptor tyrosine-protein kinase TNK1 (TNK1).	[1]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the phosphorylation of Non-receptor tyrosine-protein kinase TNK1 (TNK1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Non-receptor tyrosine-protein kinase TNK1 (TNK1).	[5]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Non-receptor tyrosine-protein kinase TNK1 (TNK1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Non-receptor tyrosine-protein kinase TNK1 (TNK1).	[2]
Selenium	DM25CGV	Approved	Selenium increases the expression of Non-receptor tyrosine-protein kinase TNK1 (TNK1).	[3]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Non-receptor tyrosine-protein kinase TNK1 (TNK1).	[6]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Non-receptor tyrosine-protein kinase TNK1 (TNK1).	[8]

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] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [3] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [4] 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.
• [5] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [6] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [7] 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.
• [8] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [9] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.