Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUEZLO8)

• DOT Name: NUAK family SNF1-like kinase 2 (NUAK2)
• Synonyms: EC 2.7.11.1; Omphalocele kinase 2; SNF1/AMP kinase-related kinase; SNARK
• Gene Name: NUAK2
• Related Disease: Anencephaly 2
• UniProt ID: NUAK2_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MESLVFARRSGPTPSAAELARPLAEGLIKSPKPLMKKQAVKRHHHKHNLRHRYEFLETLG
  KGTYGKVKKARESSGRLVAIKSIRKDKIKDEQDLMHIRREIEIMSSLNHPHIIAIHEVFE
  NSSKIVIVMEYASRGDLYDYISERQQLSEREARHFFRQIVSAVHYCHQNRVVHRDLKLEN
  ILLDANGNIKIADFGLSNLYHQGKFLQTFCGSPLYASPEIVNGKPYTGPEVDSWSLGVLL
  YILVHGTMPFDGHDHKILVKQISNGAYREPPKPSDACGLIRWLLMVNPTRRATLEDVASH
  WWVNWGYATRVGEQEAPHEGGHPGSDSARASMADWLRRSSRPLLENGAKVCSFFKQHAPG
  GGSTTPGLERQHSLKKSRKENDMAQSLHSDTADDTAHRPGKSNLKLPKGILKKKVSASAE
  GVQEDPPELSPIPASPGQAAPLLPKKGILKKPRQRESGYYSSPEPSESGELLDAGDVFVS
  GDPKEQKPPQASGLLLHRKGILKLNGKFSQTALELAAPTTFGSLDELAPPRPLARASRPS
  GAVSEDSILSSESFDQLDLPERLPEPPLRGCVSVDNLTGLEEPPSEGPGSCLRRWRQDPL
  GDSCFSLTDCQEVTATYRQALRVCSKLT
• Function: Stress-activated kinase involved in tolerance to glucose starvation. Induces cell-cell detachment by increasing F-actin conversion to G-actin. Expression is induced by CD95 or TNF-alpha, via NF-kappa-B. Protects cells from CD95-mediated apoptosis and is required for the increased motility and invasiveness of CD95-activated tumor cells. Phosphorylates LATS1 and LATS2. Plays a key role in neural tube closure during embryonic development through LATS2 phosphorylation and regulation of the nuclear localization of YAP1 a critical downstream regulatory target in the Hippo signaling pathway.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anencephaly 2	DIS1V1OE	Limited	Autosomal recessive	[1]

17 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 NUAK family SNF1-like kinase 2 (NUAK2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[2]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[2]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[17]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of NUAK family SNF1-like kinase 2 (NUAK2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NUAK family SNF1-like kinase 2 (NUAK2).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of NUAK family SNF1-like kinase 2 (NUAK2).	[15]

References

• [1] A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling. J Exp Med. 2020 Dec 7;217(12):e20191561. doi: 10.1084/jem.20191561.
• [2] 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.
• [3] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.
• [15] 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.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [18] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.