Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1TPWQR)

• DOT Name: Soluble calcium-activated nucleotidase 1 (CANT1)
• Synonyms: SCAN-1; EC 3.6.1.6; Apyrase homolog; Putative MAPK-activating protein PM09; Putative NF-kappa-B-activating protein 107
• Gene Name: CANT1
• Related Disease:
  Desbuquois dysplasia 1
  Nervous system disease
  Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
  Advanced cancer
  Ataxia-telangiectasia
  Catel-Manzke syndrome
  Chondrodysplasia with joint dislocations, gPAPP type
  Cleft palate
  Isolated cleft palate
  Mitochondrial disease
  Multiple epiphyseal dysplasia
  Prostate cancer
  Prostate carcinoma
  Spondyloepiphyseal dysplasia
  Spondyloepiphyseal dysplasia congenita
  Uveal Melanoma
  Clear cell renal carcinoma
  Hydrops fetalis
  Desbuquois dysplasia
  Thrombosis
• UniProt ID: CANT1_HUMAN
• PDB ID: 1S18; 1S1D; 2H2N; 2H2U
• EC Number: 3.6.1.6
• Pfam ID: PF06079
• Sequence:
  MPVQLSEHPEWNESMHSLRISVGGLPVLASMTKAADPRFRPRWKVILTFFVGAAILWLLC
  SHRPAPGRPPTHNAHNWRLGQAPANWYNDTYPLSPPQRTPAGIRYRIAVIADLDTESRAQ
  EENTWFSYLKKGYLTLSDSGDKVAVEWDKDHGVLESHLAEKGRGMELSDLIVFNGKLYSV
  DDRTGVVYQIEGSKAVPWVILSDGDGTVEKGFKAEWLAVKDERLYVGGLGKEWTTTTGDV
  VNENPEWVKVVGYKGSVDHENWVSNYNALRAAAGIQPPGYLIHESACWSDTLQRWFFLPR
  RASQERYSEKDDERKGANLLLSASPDFGDIAVSHVGAVVPTHGFSSFKFIPNTDDQIIVA
  LKSEEDSGRVASYIMAFTLDGRFLLPETKIGSVKYEGIEFI
• Function: Calcium-dependent nucleotidase with a preference for UDP. The order of activity with different substrates is UDP > GDP > UTP > GTP. Has very low activity towards ADP and even lower activity towards ATP. Does not hydrolyze AMP and GMP. Involved in proteoglycan synthesis.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Desbuquois dysplasia 1	DISZMDJW	Definitive	Autosomal recessive	[1]
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[2]
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	DIS84UUI	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[4]
Catel-Manzke syndrome	DISY1VBO	Strong	Genetic Variation	[5]
Chondrodysplasia with joint dislocations, gPAPP type	DISCOG8O	Strong	Genetic Variation	[5]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[5]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[5]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[4]
Multiple epiphyseal dysplasia	DIS5FZLR	Strong	Genetic Variation	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Spondyloepiphyseal dysplasia	DIS1JG9A	Strong	Genetic Variation	[8]
Spondyloepiphyseal dysplasia congenita	DISLC6W8	Strong	Genetic Variation	[8]
Uveal Melanoma	DISA7ZGL	Strong	Biomarker	[9]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[10]
Hydrops fetalis	DISD9BBF	moderate	Genetic Variation	[11]
Desbuquois dysplasia	DISCBF04	Supportive	Autosomal recessive	[12]
Thrombosis	DIS2TXP8	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Soluble calcium-activated nucleotidase 1 (CANT1) affects the response to substance of Acetaminophen.	[23]

2 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 Soluble calcium-activated nucleotidase 1 (CANT1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Soluble calcium-activated nucleotidase 1 (CANT1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Soluble calcium-activated nucleotidase 1 (CANT1).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Soluble calcium-activated nucleotidase 1 (CANT1).	[16]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Soluble calcium-activated nucleotidase 1 (CANT1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Soluble calcium-activated nucleotidase 1 (CANT1).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Soluble calcium-activated nucleotidase 1 (CANT1).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Soluble calcium-activated nucleotidase 1 (CANT1).	[21]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Soluble calcium-activated nucleotidase 1 (CANT1).	[22]

References

• [1] Identification of CANT1 mutations in Desbuquois dysplasia. Am J Hum Genet. 2009 Nov;85(5):706-10. doi: 10.1016/j.ajhg.2009.10.001. Epub 2009 Oct 22.
• [2] Defective DNA repair and neurodegenerative disease.Cell. 2007 Sep 21;130(6):991-1004. doi: 10.1016/j.cell.2007.08.043.
• [3] Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.Nature. 2005 Mar 3;434(7029):108-13. doi: 10.1038/nature03314.
• [4] A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging.Aging (Albany NY). 2013 Mar;5(3):192-208. doi: 10.18632/aging.100546.
• [5] IMPAD1 mutations in two Catel-Manzke like patients.Am J Med Genet A. 2012 Sep;158A(9):2183-7. doi: 10.1002/ajmg.a.35504. Epub 2012 Aug 6.
• [6] MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1.Am J Med Genet A. 2017 Sep;173(9):2415-2421. doi: 10.1002/ajmg.a.38349. Epub 2017 Jul 25.
• [7] Repeatability of radiomics and machine learning for DWI: Short-term repeatability study of 112 patients with prostate cancer.Magn Reson Med. 2020 Jun;83(6):2293-2309. doi: 10.1002/mrm.28058. Epub 2019 Nov 8.
• [8] Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome.Eur J Hum Genet. 2015 Jan;23(1):49-53. doi: 10.1038/ejhg.2014.60. Epub 2014 Apr 23.
• [9] CANT1 lncRNA Triggers Efficient Therapeutic Efficacy by Correcting Aberrant lncing Cascade in Malignant Uveal Melanoma.Mol Ther. 2017 May 3;25(5):1209-1221. doi: 10.1016/j.ymthe.2017.02.016. Epub 2017 Mar 18.
• [10] Calcium-activated nucleotidase 1 silencing inhibits proliferation, migration, and invasion in human clear cell renal cell carcinoma.J Cell Physiol. 2019 Dec;234(12):22635-22647. doi: 10.1002/jcp.28829. Epub 2019 May 17.
• [11] Desbuquois dysplasia type I and fetal hydrops due to novel mutations in the CANT1 gene.Eur J Hum Genet. 2011 Nov;19(11):1133-7. doi: 10.1038/ejhg.2011.101. Epub 2011 Jun 8.
• [12] Further delineation of CANT1 phenotypic spectrum and demonstration of its role in proteoglycan synthesis. Hum Mutat. 2012 Aug;33(8):1261-6. doi: 10.1002/humu.22104. Epub 2012 May 22.
• [13] Engineered human soluble calcium-activated nucleotidase inhibits coagulation in vitro and thrombosis in vivo.Thromb Res. 2008;122(4):541-8. doi: 10.1016/j.thromres.2007.12.002. Epub 2008 Jan 28.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] 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.
• [23] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.