Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI495RD)

• DOT Name: C2 domain-containing protein 5 (C2CD5)
• Synonyms: C2 domain-containing phosphoprotein of 138 kDa
• Gene Name: C2CD5
• Related Disease:
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Obesity
• UniProt ID: C2CD5_HUMAN
• Pfam ID: PF00168
• Sequence:
  MPGKLKVKIVAGRHLPVMDRASDLTDAFVEVKFGNTTFKTDVYLKSLNPQWNSEWFKFEV
  DDEDLQDEPLQITVLDHDTYSANDAIGKVYIDIDPLLYSEAATVISGWFPIYDTIHGIRG
  EINVVVKVDLFNDLNRFRQSSCGVKFFCTTSIPKCYRAVIIHGFVEELVVNEDPEYQWID
  RIRTPRASNEARQRLISLMSGELQRKIGLKVLEMRGNAVVGYLQCFDLEGESGLVVRAIG
  TACTLDKLSSPAAFLPACNSPSKEMKEIPFNEDPNPNTHSSGPSTPLKNQTYSFSPSKSY
  SRQSSSSDTDLSLTPKTGMGSGSAGKEGGPFKALLRQQTQSALEQREFPFFTLTAFPPGF
  LVHVGGVVSARSVKLLDRIHNPDEPETRDAWWAEIRQEIKSHAKALGCHAVVGYSESTSI
  CEEVCILSASGTAAVLNPRFLQDGTVEGCLEQRLEENLPTRCGFCHIPYDELNMPFPAHL
  TYCYNCRKQKVPDVLFTTIDLPTDATVIGKGCLIQARLCRLKKKAQAEANATAISNLLPF
  MEYEVHTQLMNKLKLKGMNALFGLRIQITVGENMLMGLASATGVYLAALPTPGGIQIAGK
  TPNDGSYEQHISHMQKKINDTIAKNKELYEINPPEISEEIIGSPIPEPRQRSRLLRSQSE
  SSDEVTELDLSHGKKDAFVLEIDDTDAMEDVHSLLTDVPPPSGFYSCNTEIMPGINNWTS
  EIQMFTSVRVIRLSSLNLTNQALNKNFNDLCENLLKSLYFKLRSMIPCCLCHVNFTVSLP
  EDELIQVTVTAVAITFDKNQALQTTKTPVEKSLQRASTDNEELLQFPLELCSDSLPSHPF
  PPAKAMTVEKASPVGDGNFRNRSAPPCANSTVGVVKMTPLSFIPGAKITKYLGIINMFFI
  RETTSLREEGGVSGFLHAFIAEVFAMVRAHVAALGGNAVVSYIMKQCVFMENPNKNQAQC
  LINVSGDAVVFVRESDLEVVSSQQPTTNCQSSCTEGEVTT
• Function: Required for insulin-stimulated glucose transport and glucose transporter SLC2A4/GLUT4 translocation from intracellular glucose storage vesicle (GSV) to the plasma membrane (PM) in adipocytes. Binds phospholipid membranes in a calcium-dependent manner and is necessary for the optimal membrane fusion between SLC2A4/GLUT4 GSV and the PM.
• Reactome Pathway: Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Obesity	DIS47Y1K	Strong	Biomarker	[2]

3 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 C2 domain-containing protein 5 (C2CD5).	[3]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of C2 domain-containing protein 5 (C2CD5).	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of C2 domain-containing protein 5 (C2CD5).	[13]

11 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 C2 domain-containing protein 5 (C2CD5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of C2 domain-containing protein 5 (C2CD5).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of C2 domain-containing protein 5 (C2CD5).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of C2 domain-containing protein 5 (C2CD5).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of C2 domain-containing protein 5 (C2CD5).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of C2 domain-containing protein 5 (C2CD5).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of C2 domain-containing protein 5 (C2CD5).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of C2 domain-containing protein 5 (C2CD5).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of C2 domain-containing protein 5 (C2CD5).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of C2 domain-containing protein 5 (C2CD5).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of C2 domain-containing protein 5 (C2CD5).	[14]

References

• [1] CDP138 silencing inhibits TGF-/Smad signaling to impair radioresistance and metastasis via GDF15 in lung cancer.Cell Death Dis. 2017 Sep 7;8(9):e3036. doi: 10.1038/cddis.2017.434.
• [2] Membrane Trafficking Protein CDP138 Regulates Fat Browning and Insulin Sensitivity through Controlling Catecholamine Release.Mol Cell Biol. 2018 Mar 29;38(8):e00153-17. doi: 10.1128/MCB.00153-17. Print 2018 Apr 15.
• [3] 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.
• [4] 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.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.