Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3SBS2S)

• DOT Name: Dihydropyrimidinase-related protein 4 (DPYSL4)
• Synonyms: DRP-4; Collapsin response mediator protein 3; CRMP-3; UNC33-like phosphoprotein 4; ULIP-4
• Gene Name: DPYSL4
• Related Disease:
  Advanced cancer
  Endometrial cancer
  Endometrial carcinoma
  Glioblastoma multiforme
  Neoplasm
  Obesity
• UniProt ID: DPYL4_HUMAN
• PDB ID: 5NKS
• Pfam ID: PF01979
• Sequence:
  MSFQGKKSIPRITSDRLLIRGGRIVNDDQSFYADVHVEDGLIKQIGENLIVPGGIKTIDA
  HGLMVLPGGVDVHTRLQMPVLGMTPADDFCQGTKAALAGGTTMILDHVFPDTGVSLLAAY
  EQWRERADSAACCDYSLHVDITRWHESIKEELEALVKEKGVNSFLVFMAYKDRCQCSDSQ
  MYEIFSIIRDLGALAQVHAENGDIVEEEQKRLLELGITGPEGHVLSHPEEVEAEAVYRAV
  TIAKQANCPLYVTKVMSKGAADAIAQAKRRGVVVFGEPITASLGTDGSHYWSKNWAKAAA
  FVTSPPVNPDPTTADHLTCLLSSGDLQVTGSAHCTFTTAQKAVGKDNFALIPEGTNGIEE
  RMSMVWEKCVASGKMDENEFVAVTSTNAAKIFNFYPRKGRVAVGSDADLVIWNPKATKII
  SAKTHNLNVEYNIFEGVECRGAPAVVISQGRVALEDGKMFVTPGAGRFVPRKTFPDFVYK
  RIKARNRLAEIHGVPRGLYDGPVHEVMVPAKPGSGAPARASCPGKISVPPVRNLHQSGFS
  LSGSQADDHIARRTAQKIMAPPGGRSNITSLS
• Function: Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, neuronal growth cone collapse and cell migration.
• Reactome Pathway: CRMPs in Sema3A signaling (R-HSA-399956)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[2]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Obesity	DIS47Y1K	Strong	Biomarker	[1]

1 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 Dihydropyrimidinase-related protein 4 (DPYSL4).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[14]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[15]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[16]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[15]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Dihydropyrimidinase-related protein 4 (DPYSL4).	[18]

References

• [1] p53-inducible DPYSL4 associates with mitochondrial supercomplexes and regulates energy metabolism in adipocytes and cancer cells.Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):8370-8375. doi: 10.1073/pnas.1804243115. Epub 2018 Jul 30.
• [2] Quantitative DNA methylation analysis of selected genes in endometrial carcinogenesis.Taiwan J Obstet Gynecol. 2015 Oct;54(5):572-9. doi: 10.1016/j.tjog.2015.08.010.
• [3] Ulip/CRMP proteins are recognized by autoantibodies in paraneoplastic neurological syndromes.Eur J Neurosci. 1999 Dec;11(12):4226-32. doi: 10.1046/j.1460-9568.1999.00864.x.
• [4] 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.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [16] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [17] 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.
• [18] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.