Details of Drug Off-Target (DOT)

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

• DOT Name: NUAK family SNF1-like kinase 1 (NUAK1)
• Synonyms: EC 2.7.11.1; AMPK-related protein kinase 5; ARK5; Omphalocele kinase 1
• Gene Name: NUAK1
• UniProt ID: NUAK1_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MEGAAAPVAGDRPDLGLGAPGSPREAVAGATAALEPRKPHGVKRHHHKHNLKHRYELQET
  LGKGTYGKVKRATERFSGRVVAIKSIRKDKIKDEQDMVHIRREIEIMSSLNHPHIISIYE
  VFENKDKIVIIMEYASKGELYDYISERRRLSERETRHFFRQIVSAVHYCHKNGVVHRDLK
  LENILLDDNCNIKIADFGLSNLYQKDKFLQTFCGSPLYASPEIVNGRPYRGPEVDSWALG
  VLLYTLVYGTMPFDGFDHKNLIRQISSGEYREPTQPSDARGLIRWMLMVNPDRRATIEDI
  ANHWWVNWGYKSSVCDCDALHDSESPLLARIIDWHHRSTGLQADTEAKMKGLAKPTTSEV
  MLERQRSLKKSKKENDFAQSGQDAVPESPSKLSSKRPKGILKKRSNSEHRSHSTGFIEGV
  VGPALPSTFKMEQDLCRTGVLLPSSPEAEVPGKLSPKQSATMPKKGILKKTQQRESGYYS
  SPERSESSELLDSNDVMGSSIPSPSPPDPARVTSHSLSCRRKGILKHSSKYSAGTMDPAL
  VSPEMPTLESLSEPGVPAEGLSRSYSRPSSVISDDSVLSSDSFDLLDLQENRPARQRIRS
  CVSAENFLQIQDFEGLQNRPRPQYLKRYRNRLADSSFSLLTDMDDVTQVYKQALEICSKL
  N
• Function: Serine/threonine-protein kinase involved in various processes such as cell adhesion, regulation of cell ploidy and senescence, cell proliferation and tumor progression. Phosphorylates ATM, CASP6, LATS1, PPP1R12A and p53/TP53. Acts as a regulator of cellular senescence and cellular ploidy by mediating phosphorylation of 'Ser-464' of LATS1, thereby controlling its stability. Controls cell adhesion by regulating activity of the myosin protein phosphatase 1 (PP1) complex. Acts by mediating phosphorylation of PPP1R12A subunit of myosin PP1: phosphorylated PPP1R12A then interacts with 14-3-3, leading to reduced dephosphorylation of myosin MLC2 by myosin PP1. May be involved in DNA damage response: phosphorylates p53/TP53 at 'Ser-15' and 'Ser-392' and is recruited to the CDKN1A/WAF1 promoter to participate in transcription activation by p53/TP53. May also act as a tumor malignancy-associated factor by promoting tumor invasion and metastasis under regulation and phosphorylation by AKT1. Suppresses Fas-induced apoptosis by mediating phosphorylation of CASP6, thereby suppressing the activation of the caspase and the subsequent cleavage of CFLAR. Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with STK11, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair.
• Tissue Specificity: Expressed at high levels in heart and brain, and at lower levels in skeletal muscle, kidney, ovary, placenta, lung and liver. Highly up-regulated in colorectal cancer cell lines.
• Reactome Pathway: Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)

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
WZ4003	DMP9RBK	Investigative	NUAK family SNF1-like kinase 1 (NUAK1) decreases the response to substance of WZ4003.	[24]

7 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 NUAK family SNF1-like kinase 1 (NUAK1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NUAK family SNF1-like kinase 1 (NUAK1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of NUAK family SNF1-like kinase 1 (NUAK1).	[12]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of NUAK family SNF1-like kinase 1 (NUAK1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NUAK family SNF1-like kinase 1 (NUAK1).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of NUAK family SNF1-like kinase 1 (NUAK1).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of NUAK family SNF1-like kinase 1 (NUAK1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[5]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[15]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[16]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[17]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[5]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[5]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[5]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of NUAK family SNF1-like kinase 1 (NUAK1).	[23]

References

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• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] 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.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] 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.
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• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [13] 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.
• [14] 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.
• [15] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [16] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [17] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [18] 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.
• [19] 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.
• [20] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [21] 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.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [24] Characterization of WZ4003 and HTH-01-015 as selective inhibitors of the LKB1-tumour-suppressor-activated NUAK kinases. Biochem J. 2014 Jan 1;457(1):215-25.