Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0WE161)

• DOT Name: Calpain-15 (CAPN15)
• Synonyms: EC 3.4.22.-; Small optic lobes homolog
• Gene Name: CAPN15
• Related Disease:
  Cataract
  Major depressive disorder
  Oculogastrointestinal-neurodevelopmental syndrome
• UniProt ID: CAN15_HUMAN
• EC Number: 3.4.22.-
• Pfam ID: PF00648 ; PF00641
• Sequence:
  MATVGEWSCVRCTFLNPAGQRQCSICEAPRHKPDLNHILRLSVEEQKWPCARCTFRNFLG
  KEACEVCGFTPEPAPGAAFLPVLNGVLPKPPAILGEPKGSCQEEAGPVRTAGLVATEPAR
  GQCEDKDEEEKEEQEEEEGAAEPRGGWACPRCTLHNTPVASSCSVCGGPRRLSLPRIPPE
  ALVVPEVVAPAGFHVVPAAPPPGLPGEGAEANPPATSQGPAAEPEPPRVPPFSPFSSTLQ
  NNPVPRSRREVPPQLQPPVPEAAQPSPSAGCRGAPQGSGWAGASRLAELLSGKRLSVLEE
  EATEGGTSRVEAGSSTSGSDIIDLAGDTVRYTPASPSSPDFTTWSCAKCTLRNPTVAPRC
  SACGCSKLHGFQEHGEPPTHCPDCGADKPSPCGRSCGRVSSAQKAARVLPERPGQWACPA
  CTLLNALRAKHCAACHTPQLLVAQRRGAAPLRRRESMHVEQRRQTDEGEAKALWENIVAF
  CRENNVSFVDDSFPPGPESVGFPAGDSVQQRVRQWLRPQEINCSVFRDHRATWSVFHTLR
  PSDILQGLLGNCWFLSALAVLAERPDLVERVMVTRSLCAEGAYQVRLCKDGTWTTVLVDD
  MLPCDEAGCLLFSQAQRKQLWVALIEKALAKLHGSYFALQAGRAIEGLATLTGAPCESLA
  LQLSSTNPREEPVDTDLIWAKMLSSKEAGFLMGASCGGGNMKVDDSAYESLGLRPRHAYS
  ILDVRDVQGTRLLRLRNPWGRFSWNGSWSDEWPHWPGHLRGELMPHGSSEGVFWMEYGDF
  VRYFDSVDICKVHSDWQEARVQGCFPSSASAPVGVTALTVLERASLEFALFQEGSRRSDA
  VDSHLLDLCILVFRATFGSGGHLSLGRLLAHSKRAVKKFVSCDVMLEPGEYAVVCCAFNH
  WGPPLPGTPAPQASSPSAGVPRASPEPPGHVLAVYSSRLVMVEPVEAQPTTLADAIILLT
  ESRGERHEGREGMTCYYLTHGWAGLIVVVENRHPKAYLHVQCDCTDSFNVVSTRGSLRTQ
  DSVPPLHRQVLVILSQLEGNAGFSITHRLAHRKAAQAFLSDWTASKGTHSPPLTPEVAGL
  HGPRPL
• Tissue Specificity: Widely expressed with higher expression in brain.
• Reactome Pathway: Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract	DISUD7SL	Strong	Biomarker	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[2]
Oculogastrointestinal-neurodevelopmental syndrome	DIS588HX	Strong	Autosomal recessive	[3]

5 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 Calpain-15 (CAPN15).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Calpain-15 (CAPN15).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Calpain-15 (CAPN15).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Calpain-15 (CAPN15).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Calpain-15 (CAPN15).	[16]

9 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 Calpain-15 (CAPN15).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Calpain-15 (CAPN15).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calpain-15 (CAPN15).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Calpain-15 (CAPN15).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Calpain-15 (CAPN15).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Calpain-15 (CAPN15).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Calpain-15 (CAPN15).	[8]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Calpain-15 (CAPN15).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Calpain-15 (CAPN15).	[14]

References

• [1] SOLH, a human homologue of the Drosophila melanogaster small optic lobes gene is a member of the calpain and zinc-finger gene families and maps to human chromosome 16p13.3 near CATM (cataract with microphthalmia).Genomics. 1998 Jul 15;51(2):197-206. doi: 10.1006/geno.1998.5395.
• [2] GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.Am J Psychiatry. 2019 Aug 1;176(8):651-660. doi: 10.1176/appi.ajp.2019.18080957. Epub 2019 Jun 5.
• [3] Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits. Hum Mol Genet. 2020 Nov 4;29(18):3054-3063. doi: 10.1093/hmg/ddaa198.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [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] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.