Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV1FW0M)

• DOT Name: Calcium-dependent secretion activator 2 (CADPS2)
• Synonyms: Calcium-dependent activator protein for secretion 2; CAPS-2
• Gene Name: CADPS2
• Related Disease:
  Alzheimer disease
  Cardiovascular disease
  Cholestasis
  Drug dependence
  Epilepsy
  Intellectual disability
  Mental disorder
  Nervous system disease
  Parkinson disease
  Persistent hyperplastic primary vitreous
  Pervasive developmental disorder
  Schizophrenia
  Substance abuse
  Substance dependence
  Autism
  Autism spectrum disorder
• UniProt ID: CAPS2_HUMAN
• Pfam ID: PF06292 ; PF00169
• Sequence:
  MLDPSSSEEESDEGLEEESRDVLVAAGSSQRAPPAPTREGRRDAPGRAGGGGAARSVSPS
  PSVLSEGRDEPQRQLDDEQERRIRLQLYVFVVRCIAYPFNAKQPTDMARRQQKLNKQQLQ
  LLKERFQAFLNGETQIVADEAFCNAVRSYYEVFLKSDRVARMVQSGGCSANDFREVFKKN
  IEKRVRSLPEIDGLSKETVLSSWIAKYDAIYRGEEDLCKQPNRMALSAVSELILSKEQLY
  EMFQQILGIKKLEHQLLYNACQLDNADEQAAQIRRELDGRLQLADKMAKERKFPKFIAKD
  MENMYIEELRSSVNLLMANLESLPVSKGGPEFKLQKLKRSQNSAFLDIGDENEIQLSKSD
  VVLSFTLEIVIMEVQGLKSVAPNRIVYCTMEVEGEKLQTDQAEASRPQWGTQGDFTTTHP
  RPVVKVKLFTESTGVLALEDKELGRVILYPTSNSSKSAELHRMVVPKNSQDSDLKIKLAV
  RMDKPAHMKHSGYLYALGQKVWKRWKKRYFVLVQVSQYTFAMCSYREKKSEPQELMQLEG
  YTVDYTDPHPGLQGGCMFFNAVKEGDTVIFASDDEQDRILWVQAMYRATGQSYKPVPAIQ
  TQKLNPKGGTLHADAQLSGKDADRFQKHGMDEFISANPCKLDHAFLFRILQRQTLDHRLN
  DSYSCLGWFSPGQVFVLDEYCARYGVRGCHRHLCYLAELMEHSENGAVIDPTLLHYSFAF
  CASHVHGNRPDGIGTVSVEEKERFEEIKERLSSLLENQISHFRYCFPFGRPEGALKATLS
  LLERVLMKDIATPIPAEEVKKVVRKCLEKAALINYTRLTEYAKIEETMNQASPARKLEEI
  LHLAELCIEVLQQNEEHHAEGREAFAWWPDLLAEHAEKFWALFTVDMDTALEAQPQDSWD
  SFPLFQLLNNFLRNDTLLCNGKFHKHLQEIFVPLVVRYVDLMESSIAQSIHRGFEQETWQ
  PVKNIANSLPNVALPKVPSLPLNLPQIPNISTASWMPSLYESTNGSATSEDLFWKLDALQ
  MFVFDLHWPEQEFAHHLEQRLKLMASDMLEACVKRTRTAFELKLQKASKTTDLRIPASVC
  TMFNVLVDAKKQSTKLCALDGGQEQQYHSKIDDLIDNSVKEIISLLVSKFVSVLEGVLSK
  LSRYDEGTFFSSILSFTVKAAAKYVDVPKPGMDLADTYIMFVRQNQDILREKVNEEMYIE
  KLFDQWYSSSMKVICVWLTDRLDLQLHIYQLKTLIKIVKKTYRDFRLQGVLEGTLNSKTY
  DTVHRRLTVEEATASVSEGGGLQGITMKDSDEEEEG
• Function: Calcium-binding protein involved in exocytosis of vesicles filled with neurotransmitters and neuropeptides. Probably acts upstream of fusion in the biogenesis or maintenance of mature secretory vesicles. Regulates neurotrophin release from granule cells leading to regulate cell differentiation and survival during cerebellar development. May specifically mediate the Ca(2+)-dependent exocytosis of large dense-core vesicles (DCVs) and other dense-core vesicles.
• Tissue Specificity: Widely expressed. Expressed in all adult and fetal tissues examined, with the strongest expression in kidney and pancreas. In brain, it is expressed at high levels in cerebellum, to a lesser degree in cerebral cortex, occipital pole, and frontal and temporal lobes. Only weakly expressed in medulla, spinal cord and putamen.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Definitive	Genetic Variation	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[2]
Cholestasis	DISDJJWE	Strong	Biomarker	[3]
Drug dependence	DIS9IXRC	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Mental disorder	DIS3J5R8	Strong	Altered Expression	[6]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[7]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[1]
Persistent hyperplastic primary vitreous	DISABPH6	Strong	Biomarker	[8]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]
Substance abuse	DIS327VW	Strong	Biomarker	[4]
Substance dependence	DISDRAAR	Strong	Biomarker	[4]
Autism	DISV4V1Z	Limited	Genetic Variation	[9]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[7]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Calcium-dependent secretion activator 2 (CADPS2) affects the response to substance of Etoposide.	[24]
Mitomycin	DMH0ZJE	Approved	Calcium-dependent secretion activator 2 (CADPS2) affects the response to substance of Mitomycin.	[24]

13 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 Calcium-dependent secretion activator 2 (CADPS2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[15]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Calcium-dependent secretion activator 2 (CADPS2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Calcium-dependent secretion activator 2 (CADPS2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Calcium-dependent secretion activator 2 (CADPS2).	[20]

References

• [1] CADPS2 gene expression is oppositely regulated by LRRK2 and alpha-synuclein.Biochem Biophys Res Commun. 2017 Aug 26;490(3):876-881. doi: 10.1016/j.bbrc.2017.06.134. Epub 2017 Jun 21.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Classification of Cholestatic and Necrotic Hepatotoxicants Using Transcriptomics on Human Precision-Cut Liver Slices.Chem Res Toxicol. 2016 Mar 21;29(3):342-51. doi: 10.1021/acs.chemrestox.5b00491. Epub 2016 Mar 9.
• [4] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [5] Maternally inherited genetic variants of CADPS2 are present in autism spectrum disorders and intellectual disability patients.EMBO Mol Med. 2014 Jun;6(6):795-809. doi: 10.1002/emmm.201303235. Epub 2014 Apr 6.
• [6] Expression of Ca?dependent activator protein for secretion 2 is increased in the brains of schizophrenic patients.Prog Neuropsychopharmacol Biol Psychiatry. 2011 Aug 15;35(7):1738-43. doi: 10.1016/j.pnpbp.2011.05.004. Epub 2011 May 12.
• [7] 7q31.32 partial duplication: First report of a child with dysmorphism, autistic spectrum disorder, moderate intellectual disability and, epilepsy. Literature review.Epilepsy Res. 2019 Dec;158:106223. doi: 10.1016/j.eplepsyres.2019.106223. Epub 2019 Nov 1.
• [8] Submicroscopic deletion in 7q31 encompassing CADPS2 and TSPAN12 in a child with autism spectrum disorder and PHPV.Am J Med Genet A. 2011 Jul;155A(7):1568-73. doi: 10.1002/ajmg.a.34028. Epub 2011 May 27.
• [9] Blood CADPS2Exon3 expression is associated with intelligence and memory in healthy adults.Biol Psychol. 2012 Jan;89(1):117-22. doi: 10.1016/j.biopsycho.2011.09.017. Epub 2011 Oct 12.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [17] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [18] 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.
• [19] 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.
• [20] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] 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.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.