Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDZBJ4K)

• DOT Name: TRAF2 and NCK-interacting protein kinase (TNIK)
• Synonyms: EC 2.7.11.1
• Gene Name: TNIK
• Related Disease:
  Autosomal recessive non-syndromic intellectual disability
  Intellectual disability, autosomal recessive 54
• UniProt ID: TNIK_HUMAN
• PDB ID: 2X7F; 5AX9; 5CWZ; 5D7A; 6RA5; 6RA7; 7XZQ; 7XZR
• EC Number: 2.7.11.1
• Pfam ID: PF00780 ; PF00069
• Sequence:
  MASDSPARSLDEIDLSALRDPAGIFELVELVGNGTYGQVYKGRHVKTGQLAAIKVMDVTG
  DEEEEIKQEINMLKKYSHHRNIATYYGAFIKKNPPGMDDQLWLVMEFCGAGSVTDLIKNT
  KGNTLKEEWIAYICREILRGLSHLHQHKVIHRDIKGQNVLLTENAEVKLVDFGVSAQLDR
  TVGRRNTFIGTPYWMAPEVIACDENPDATYDFKSDLWSLGITAIEMAEGAPPLCDMHPMR
  ALFLIPRNPAPRLKSKKWSKKFQSFIESCLVKNHSQRPATEQLMKHPFIRDQPNERQVRI
  QLKDHIDRTKKKRGEKDETEYEYSGSEEEEEENDSGEPSSILNLPGESTLRRDFLRLQLA
  NKERSEALRRQQLEQQQRENEEHKRQLLAERQKRIEEQKEQRRRLEEQQRREKELRKQQE
  REQRRHYEEQMRREEERRRAEHEQEYIRRQLEEEQRQLEILQQQLLHEQALLLEYKRKQL
  EEQRQAERLQRQLKQERDYLVSLQHQRQEQRPVEKKPLYHYKEGMSPSEKPAWAKEVEER
  SRLNRQSSPAMPHKVANRISDPNLPPRSESFSISGVQPARTPPMLRPVDPQIPHLVAVKS
  QGPALTASQSVHEQPTKGLSGFQEALNVTSHRVEMPRQNSDPTSENPPLPTRIEKFDRSS
  WLRQEEDIPPKVPQRTTSISPALARKNSPGNGSALGPRLGSQPIRASNPDLRRTEPILES
  PLQRTSSGSSSSSSTPSSQPSSQGGSQPGSQAGSSERTRVRANSKSEGSPVLPHEPAKVK
  PEESRDITRPSRPASYKKAIDEDLTALAKELRELRIEETNRPMKKVTDYSSSSEESESSE
  EEEEDGESETHDGTVAVSDIPRLIPTGAPGSNEQYNVGMVGTHGLETSHADSFSGSISRE
  GTLMIRETSGEKKRSGHSDSNGFAGHINLPDLVQQSHSPAGTPTEGLGRVSTHSQEMDSG
  TEYGMGSSTKASFTPFVDPRVYQTSPTDEDEEDEESSAAALFTSELLRQEQAKLNEARKI
  SVVNVNPTNIRPHSDTPEIRKYKKRFNSEILCAALWGVNLLVGTENGLMLLDRSGQGKVY
  NLINRRRFQQMDVLEGLNVLVTISGKKNKLRVYYLSWLRNRILHNDPEVEKKQGWITVGD
  LEGCIHYKVVKYERIKFLVIALKNAVEIYAWAPKPYHKFMAFKSFADLQHKPLLVDLTVE
  EGQRLKVIFGSHTGFHVIDVDSGNSYDIYIPSHIQGNITPHAIVILPKTDGMEMLVCYED
  EGVYVNTYGRITKDVVLQWGEMPTSVAYIHSNQIMGWGEKAIEIRSVETGHLDGVFMHKR
  AQRLKFLCERNDKVFFASVRSGGSSQVFFMTLNRNSMMNW
• Function: Serine/threonine kinase that acts as an essential activator of the Wnt signaling pathway. Recruited to promoters of Wnt target genes and required to activate their expression. May act by phosphorylating TCF4/TCF7L2. Appears to act upstream of the JUN N-terminal pathway. May play a role in the response to environmental stress. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. More generally, it may play a role in cytoskeletal rearrangements and regulate cell spreading. Phosphorylates SMAD1 on Thr-322.
• Tissue Specificity: Expressed ubiquitously. Highest levels observed in heart, brain and skeletal muscle. Expressed in normal colonic epithelia and colorectal cancer tissues.
• Reactome Pathway: Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[1]
Intellectual disability, autosomal recessive 54	DIS13N99	Limited	Autosomal recessive	[2]

18 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 TRAF2 and NCK-interacting protein kinase (TNIK).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[8]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[12]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[17]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of TRAF2 and NCK-interacting protein kinase (TNIK).	[18]

1 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 TRAF2 and NCK-interacting protein kinase (TNIK).	[15]

References

• [1] A null mutation in TNIK defines a novel locus for intellectual disability. Hum Genet. 2016 Jul;135(7):773-8. doi: 10.1007/s00439-016-1671-9. Epub 2016 Apr 22.
• [2] 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.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [11] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [12] 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.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] 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.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.