Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7S3B3P)

• DOT Name: S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER)
• Synonyms: S phase cyclin A-associated protein in the ER; Zinc finger protein 291
• Gene Name: SCAPER
• Related Disease:
  Age-related macular degeneration
  Attention deficit hyperactivity disorder
  Brachydactyly
  Intellectual developmental disorder and retinitis pigmentosa; IDDRP
  Large cell lymphoma
  Neuroblastoma
  Obesity
  Intellectual disability
  Bardet biedl syndrome
  Retinitis pigmentosa
  Acute myelogenous leukaemia
• UniProt ID: SCAPE_HUMAN
• PDB ID: 8BPO
• Pfam ID: PF16501 ; PF12874
• Sequence:
  MMASFQRSNSHDKVRRIVAEEGRTARNLIAWSVPLESKDDDGKPKCQTGGKSKRTIQGTH
  KTTKQSTAVDCKITSSTTGDKHFDKSPTKTRHPRKIDLRARYWAFLFDNLRRAVDEIYVT
  CESDQSVVECKEVLMMLDNYVRDFKALIDWIQLQEKLEKTDAQSRPTSLAWEVKKMSPGR
  HVIPSPSTDRINVTSNARRSLNFGGSTGTVPAPRLAPTGVSWADKVKAHHTGSTASSEIT
  PAQSCPPMTVQKASRKNERKDAEGWETVQRGRPIRSRSTAVMPKVSLATEATRSKDDSDK
  ENVCLLPDESIQKGQFVGDGTSNTIESHPKDSLHSCDHPLAEKTQFTVSTLDDVKNSGSI
  RDNYVRTSEISAVHIDTECVSVMLQAGTPPLQVNEEKFPAEKARIENEMDPSDISNSMAE
  VLAKKEELADRLEKANEEAIASAIAEEEQLTREIEAEENNDINIETDNDSDFSASMGSGS
  VSFCGMSMDWNDVLADYEARESWRQNTSWGDIVEEEPARPPGHGIHMHEKLSSPSRKRTI
  AESKKKHEEKQMKAQQLREKLREEKTLKLQKLLEREKDVRKWKEELLDQRRRMMEEKLLH
  AEFKREVQLQAIVKKAQEEEAKVNEIAFINTLEAQNKRHDVLSKLKEYEQRLNELQEERQ
  RRQEEKQARDEAVQERKRALEAERQARVEELLMKRKEQEARIEQQRQEKEKAREDAARER
  ARDREERLAALTAAQQEAMEELQKKIQLKHDESIRRHMEQIEQRKEKAAELSSGRHANTD
  YAPKLTPYERKKQCSLCNVLISSEVYLFSHVKGRKHQQAVRENTSIQGRELSDEEVEHLS
  LKKYIIDIVVESTAPAEALKDGEERQKNKKKAKKIKARMNFRAKEYESLMETKNSGSDSP
  YKAKLQRLAKDLLKQVQVQDSGSWANNKVSALDRTLGEITRILEKENVADQIAFQAAGGL
  TALEHILQAVVPATNVNTVLRIPPKSLCNAINVYNLTCNNCSENCSDVLFSNKITFLMDL
  LIHQLTVYVPDENNTILGRNTNKQVFEGLTTGLLKVSAVVLGCLIANRPDGNCQPATPKI
  PTQEMKNKPSQGDPFNNRVQDLISYVVNMGLIDKLCACFLSVQGPVDENPKMAIFLQHAA
  GLLHAMCTLCFAVTGRSYSIFDNNRQDPTGLTAALQATDLAGVLHMLYCVLFHGTILDPS
  TASPKENYTQNTIQVAIQSLRFFNSFAALHLPAFQSIVGAEGLSLAFRHMASSLLGHCSQ
  VSCESLLHEVIVCVGYFTVNHPDNQVIVQSGRHPTVLQKLCQLPFQYFSDPRLIKVLFPS
  LIAACYNNHQNKIILEQEMSCVLLATFIQDLAQTPGQAENQPYQPKGKCLGSQDYLELAN
  RFPQQAWEEARQFFLKKEKK
• Function: CCNA2/CDK2 regulatory protein that transiently maintains CCNA2 in the cytoplasm.
• Tissue Specificity: Widely expressed with high expression in testis. Isoform 1 is detected in various tissues, including retina, fetal and adult brain. Isoform 2 is expressed in the retina at high levels, and in the brain at very low levels .

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[1]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	CausalMutation	[2]
Brachydactyly	DIS2533F	Strong	CausalMutation	[3]
Intellectual developmental disorder and retinitis pigmentosa; IDDRP	DISWC0HQ	Strong	Autosomal recessive	[2]
Large cell lymphoma	DISYZHCP	Strong	Biomarker	[4]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[3]
Obesity	DIS47Y1K	Strong	CausalMutation	[3]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[3]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[3]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER) affects the response to substance of Estradiol.	[22]

15 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 S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[21]

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 S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of S phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER).	[19]

References

• [1] Epistatic module detection for case-control studies: a Bayesian model with a Gibbs sampling strategy.PLoS Genet. 2009 May;5(5):e1000464. doi: 10.1371/journal.pgen.1000464. Epub 2009 May 1.
• [2] Mutations in SCAPER cause autosomal recessive retinitis pigmentosa with intellectual disability. J Med Genet. 2017 Sep 18;54(10):698-704. doi: 10.1136/jmedgenet-2017-104632. Epub 2017 Aug 9.
• [3] SCAPER localizes to primary cilia and its mutation affects cilia length, causing Bardet-Biedl syndrome. Eur J Hum Genet. 2019 Jun;27(6):928-940. doi: 10.1038/s41431-019-0347-z. Epub 2019 Feb 5.
• [4] High-resolution genomic profiling reveals clonal evolution and competition in gastrointestinal marginal zone B-cell lymphoma and its large cell variant.Int J Cancer. 2013 Feb 1;132(3):E116-27. doi: 10.1002/ijc.27774. Epub 2012 Sep 1.
• [5] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] 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.
• [9] 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.
• [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] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [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] 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.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.