Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNG467B)

• DOT Name: Dual specificity protein phosphatase 10 (DUSP10)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; Mitogen-activated protein kinase phosphatase 5; MAP kinase phosphatase 5; MKP-5
• Gene Name: DUSP10
• UniProt ID: DUS10_HUMAN
• PDB ID: 1ZZW; 2OUC; 2OUD; 3TG1; 6MC1; 7U4O; 7U4R; 7UMU; 7UMV; 7UN0; 7UN4; 7Y4B; 7Y4C; 7Y4D; 7Y4E
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782 ; PF00581
• Sequence:
  MPPSPLDDRVVVALSRPVRPQDLNLCLDSSYLGSANPGSNSHPPVIATTVVSLKAANLTY
  MPSSSGSARSLNCGCSSASCCTVATYDKDNQAQTQAIAAGTTTTAIGTSTTCPANQMVNN
  NENTGSLSPSSGVGSPVSGTPKQLASIKIIYPNDLAKKMTKCSKSHLPSQGPVIIDCRPF
  MEYNKSHIQGAVHINCADKISRRRLQQGKITVLDLISCREGKDSFKRIFSKEIIVYDENT
  NEPSRVMPSQPLHIVLESLKREGKEPLVLKGGLSSFKQNHENLCDNSLQLQECREVGGGA
  SAASSLLPQPIPTTPDIENAELTPILPFLFLGNEQDAQDLDTMQRLNIGYVINVTTHLPL
  YHYEKGLFNYKRLPATDSNKQNLRQYFEEAFEFIEEAHQCGKGLLIHCQAGVSRSATIVI
  AYLMKHTRMTMTDAYKFVKGKRPIISPNLNFMGQLLEFEEDLNNGVTPRILTPKLMGVET
  VV
• Function: Protein phosphatase involved in the inactivation of MAP kinases. Has a specificity for the MAPK11/MAPK12/MAPK13/MAPK14 subfamily. It preferably dephosphorylates p38.
• Tissue Specificity: Expressed in keratinocytes (at protein level) . Detected in brain .
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)
• 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

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Dual specificity protein phosphatase 10 (DUSP10).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Dual specificity protein phosphatase 10 (DUSP10).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Dual specificity protein phosphatase 10 (DUSP10).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[3]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[8]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[3]
Thalidomide	DM70BU5	Approved	Thalidomide increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[14]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[8]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[15]
Febuxostat	DMDEXQ0	Approved	Febuxostat increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[19]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[20]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[21]
HMPL-004	DM29XGY	Phase 3	HMPL-004 increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[22]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[23]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[7]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[28]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[29]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[30]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[8]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[3]
gingerol	DMNXYSM	Investigative	gingerol increases the expression of Dual specificity protein phosphatase 10 (DUSP10).	[18]

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] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [4] 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.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [8] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Inflammation in methotrexate-induced pulmonary toxicity occurs via the p38 MAPK pathway. Toxicology. 2009 Feb 27;256(3):183-90. doi: 10.1016/j.tox.2008.11.016. Epub 2008 Nov 28.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells. Lipids Health Dis. 2010 Jun 2;9:56. doi: 10.1186/1476-511X-9-56.
• [15] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [16] Febuxostat Increases Ventricular Arrhythmogenesis Through Calcium Handling Dysregulation in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Toxicol Sci. 2022 Sep 24;189(2):216-224. doi: 10.1093/toxsci/kfac073.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated by MAP kinase phosphatase-5 in prostate cells. Carcinogenesis. 2007 Jun;28(6):1188-96. doi: 10.1093/carcin/bgl241. Epub 2006 Dec 6.
• [19] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [20] Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther. 2005 Feb;4(2):233-41.
• [21] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [22] Andrographolide inhibits hypoxia-induced hypoxia-inducible factor 1 and endothelin 1 expression through the heme oxygenase 1/CO/cGMP/MKP-5 pathways in EA.hy926 cells. Environ Toxicol. 2018 Mar;33(3):269-279. doi: 10.1002/tox.22514. Epub 2017 Nov 22.
• [23] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [24] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] 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.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] 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.
• [29] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [30] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.