Details of Drug Off-Target (DOT)

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

• DOT Name: Serine/threonine-protein kinase Sgk2 (SGK2)
• Synonyms: EC 2.7.11.1; Serum/glucocorticoid-regulated kinase 2
• Gene Name: SGK2
• Related Disease:
  Bladder cancer
  Hepatocellular carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Kidney cancer
  Renal carcinoma
  Renal cell carcinoma
• UniProt ID: SGK2_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF00433
• Sequence:
  MNSSPAGTPSPQPSRANGNINLGPSANPNAQPTDFDFLKVIGKGNYGKVLLAKRKSDGAF
  YAVKVLQKKSILKKKEQSHIMAERSVLLKNVRHPFLVGLRYSFQTPEKLYFVLDYVNGGE
  LFFHLQRERRFLEPRARFYAAEVASAIGYLHSLNIIYRDLKPENILLDCQGHVVLTDFGL
  CKEGVEPEDTTSTFCGTPEYLAPEVLRKEPYDRAVDWWCLGAVLYEMLHGLPPFYSQDVS
  QMYENILHQPLQIPGGRTVAACDLLQSLLHKDQRQRLGSKADFLEIKNHVFFSPINWDDL
  YHKRLTPPFNPNVTGPADLKHFDPEFTQEAVSKSIGCTPDTVASSSGASSAFLGFSYAPE
  DDDILDC
• Function: Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, survival and proliferation. Up-regulates Na(+) channels: SCNN1A/ENAC, K(+) channels: KCNA3/Kv1.3, KCNE1 and KCNQ1, amino acid transporter: SLC6A19, glutamate transporter: SLC1A6/EAAT4, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase.
• Tissue Specificity: Highly expressed in liver, kidney and pancreas, and at lower levels in brain.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  PI3K-Akt sig.ling pathway (hsa04151)
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]
Kidney cancer	DISBIPKM	moderate	Biomarker	[3]
Renal carcinoma	DISER9XT	moderate	Biomarker	[3]
Renal cell carcinoma	DISQZ2X8	moderate	Altered Expression	[3]

18 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 Serine/threonine-protein kinase Sgk2 (SGK2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[14]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[14]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[15]
Ampicillin	DMHWE7P	Approved	Ampicillin decreases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[19]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[20]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Serine/threonine-protein kinase Sgk2 (SGK2).	[16]

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 Serine/threonine-protein kinase Sgk2 (SGK2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine/threonine-protein kinase Sgk2 (SGK2).	[18]

References

• [1] Glucocorticoid-Inducible Kinase 2 Promotes Bladder Cancer Cell Proliferation, Migration and Invasion by Enhancing -catenin/c-Myc Signaling Pathway.J Cancer. 2018 Dec 10;9(24):4774-4782. doi: 10.7150/jca.25811. eCollection 2018.
• [2] SGK2 promotes hepatocellular carcinoma progression and mediates GSK-3/-catenin signaling in HCC cells.Tumour Biol. 2017 Jun;39(6):1010428317700408. doi: 10.1177/1010428317700408.
• [3] SGK2 promotes renal cancer progression via enhancing ERK 1/2 and AKT phosphorylation.Eur Rev Med Pharmacol Sci. 2019 Apr;23(7):2756-2767. doi: 10.26355/eurrev_201904_17549.
• [4] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [5] 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.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Pretreatment of 3-MA prevents doxorubicin-induced cardiotoxicity through inhibition of autophagy initiation. Toxicology. 2023 May 15;490:153512. doi: 10.1016/j.tox.2023.153512. Epub 2023 Apr 14.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [12] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [13] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [14] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [15] Serum- and glucocorticoid-regulated kinase 2 determines drug-activated pregnane X receptor to induce gluconeogenesis in human liver cells. J Pharmacol Exp Ther. 2014 Jan;348(1):131-40. doi: 10.1124/jpet.113.209379. Epub 2013 Nov 7.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.