Details of Drug Off-Target (DOT)

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

• DOT Name: Dual specificity protein phosphatase 9 (DUSP9)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; Mitogen-activated protein kinase phosphatase 4; MAP kinase phosphatase 4; MKP-4
• Gene Name: DUSP9
• UniProt ID: DUS9_HUMAN
• PDB ID: 2HXP; 3LJ8
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782 ; PF00581
• Sequence:
  MEGLGRSCLWLRRELSPPRPRLLLLDCRSRELYESARIGGALSVALPALLLRRLRRGSLS
  VRALLPGPPLQPPPPAPVLLYDQGGGRRRRGEAEAEAEEWEAESVLGTLLQKLREEGYLA
  YYLQGGFSRFQAECPHLCETSLAGRAGSSMAPVPGPVPVVGLGSLCLGSDCSDAESEADR
  DSMSCGLDSEGATPPPVGLRASFPVQILPNLYLGSARDSANLESLAKLGIRYILNVTPNL
  PNFFEKNGDFHYKQIPISDHWSQNLSRFFPEAIEFIDEALSQNCGVLVHCLAGVSRSVTV
  TVAYLMQKLHLSLNDAYDLVKRKKSNISPNFNFMGQLLDFERSLRLEERHSQEQGSGGQA
  SAASNPPSFFTTPTSDGAFELAPT
• Function: Inactivates MAP kinases. Has a specificity for the ERK family.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway:
  Negative regulation of MAPK pathway (R-HSA-5675221)
  Signaling by MAPK mutants (R-HSA-9652817)
  RAF-independent MAPK1/3 activation (R-HSA-112409)

Molecular Interaction Atlas (MIA) of This DOT

3 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 Dual specificity protein phosphatase 9 (DUSP9).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Dual specificity protein phosphatase 9 (DUSP9).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Dual specificity protein phosphatase 9 (DUSP9).	[15]

15 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 Dual specificity protein phosphatase 9 (DUSP9).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Dual specificity protein phosphatase 9 (DUSP9).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Dual specificity protein phosphatase 9 (DUSP9).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[8]
Gefitinib	DM15F0X	Approved	Gefitinib decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[10]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Dual specificity protein phosphatase 9 (DUSP9).	[17]

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] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Identification of transcriptional biomarkers induced by SERMS in human endometrial cells using multivariate analysis of DNA microarrays. Biomarkers. 2004 Nov-Dec;9(6):447-60.
• [6] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [9] Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer. Oncol Rep. 2006 Jun;15(6):1453-60.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [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] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [17] 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.