Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG3BNOU)

• DOT Name: Anoctamin-10 (ANO10)
• Synonyms: Transmembrane protein 16K
• Gene Name: ANO10
• Related Disease:
  Nervous system disease
  Advanced cancer
  Autosomal recessive spinocerebellar ataxia 10
  Borrelia infectious disease
  Cerebellar disorder
  Coenzyme Q10 deficiency
  Gastroesophageal reflux disease
  Muscular dystrophy
  Peripheral neuropathy
  Scott syndrome
  Spinocerebellar ataxia type 10
  Central nervous system non-hodgkin lymphoma
  Cerebellar ataxia
• UniProt ID: ANO10_HUMAN
• PDB ID: 5OC9; 6R65; 6R7X; 6R7Y; 6R7Z
• Pfam ID: PF04547
• Sequence:
  MKVTLSALDTSESSFTPLVVIELAQDVKEETKEWLKNRIIAKKKDGGAQLLFRPLLNKYE
  QETLENQNLYLVGASKIRMLLGAEAVGLVKECNDNTMRAFTYRTRQNFKGFDDNNDDFLT
  MAECQFIIKHELENLRAKDEKMIPGYPQAKLYPGKSLLRRLLTSGIVIQVFPLHDSEALK
  KLEDTWYTRFALKYQPIDSIRGYFGETIALYFGFLEYFTFALIPMAVIGLPYYLFVWEDY
  DKYVIFASFNLIWSTVILELWKRGCANMTYRWGTLLMKRKFEEPRPGFHGVLGINSITGK
  EEPLYPSYKRQLRIYLVSLPFVCLCLYFSLYVMMIYFDMEVWALGLHENSGSEWTSVLLY
  VPSIIYAIVIEIMNRLYRYAAEFLTSWENHRLESAYQNHLILKVLVFNFLNCFASLFYIA
  FVLKDMKLLRQSLATLLITSQILNQIMESFLPYWLQRKHGVRVKRKVQALKADIDATLYE
  QVILEKEMGTYLGTFDDYLELFLQFGYVSLFSCVYPLAAAFAVLNNFTEVNSDALKMCRV
  FKRPFSEPSANIGVWQLAFETMSVISVVTNCALIGMSPQVNAVFPESKADLILIVVAVEH
  ALLALKFILAFAIPDKPRHIQMKLARLEFESLEALKQQQMKLVTENLKEEPMESGKEKAT
• Function: Does not exhibit calcium-activated chloride channel (CaCC) activity. Can inhibit the activity of ANO1.
• Tissue Specificity: Highly expressed in the brain. Intermediate levels in the retina and heart and low levels in the placenta, liver, lung, duodenum, kidney, testis and spleen. In brain areas, highest expression in the frontal and occipital cortices and in the cerebellum. Lower expression in the fetal brain than in the adult brain.
• Reactome Pathway:
  Induction of Cell-Cell Fusion (R-HSA-9733458)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Autosomal recessive spinocerebellar ataxia 10	DISAQ91A	Strong	Autosomal recessive	[3]
Borrelia infectious disease	DISKCYB2	Strong	Biomarker	[4]
Cerebellar disorder	DIS2O7WM	Strong	Genetic Variation	[5]
Coenzyme Q10 deficiency	DIS1HGDF	Strong	Genetic Variation	[6]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Genetic Variation	[7]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[2]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[8]
Scott syndrome	DIS4N4IB	Strong	Genetic Variation	[2]
Spinocerebellar ataxia type 10	DISEJVJK	Strong	Genetic Variation	[9]
Central nervous system non-hodgkin lymphoma	DISHGM86	Limited	Genetic Variation	[10]
Cerebellar ataxia	DIS9IRAV	Limited	Genetic Variation	[5]

1 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 Anoctamin-10 (ANO10).	[11]

12 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 Anoctamin-10 (ANO10).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Anoctamin-10 (ANO10).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Anoctamin-10 (ANO10).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Anoctamin-10 (ANO10).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Anoctamin-10 (ANO10).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Anoctamin-10 (ANO10).	[17]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Anoctamin-10 (ANO10).	[18]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Anoctamin-10 (ANO10).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Anoctamin-10 (ANO10).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Anoctamin-10 (ANO10).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Anoctamin-10 (ANO10).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Anoctamin-10 (ANO10).	[23]

References

• [1] The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K.Nat Commun. 2019 Sep 2;10(1):3956. doi: 10.1038/s41467-019-11753-1.
• [2] Physiological roles and diseases of Tmem16/Anoctamin proteins: are they all chloride channels?.Acta Pharmacol Sin. 2011 Jun;32(6):685-92. doi: 10.1038/aps.2011.48.
• [3] Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia. Am J Hum Genet. 2010 Dec 10;87(6):813-9. doi: 10.1016/j.ajhg.2010.10.015. Epub 2010 Nov 18.
• [4] A Coding Variant of ANO10, Affecting Volume Regulation of Macrophages, Is Associated with Borrelia Seropositivity.Mol Med. 2015 Feb 23;21(1):26-37. doi: 10.2119/molmed.2014.00219.
• [5] A Postural Tremor Highly Responsive to Transcranial Cerebello-Cerebral DCS in ARCA3.Front Neurol. 2017 Mar 3;8:71. doi: 10.3389/fneur.2017.00071. eCollection 2017.
• [6] ANO10 mutations cause ataxia and coenzyme Q deficiency.J Neurol. 2014 Nov;261(11):2192-8. doi: 10.1007/s00415-014-7476-7. Epub 2014 Sep 3.
• [7] Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases.Nat Commun. 2019 Sep 16;10(1):4219. doi: 10.1038/s41467-019-11968-2.
• [8] Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study.JAMA Neurol. 2014 Oct;71(10):1305-10. doi: 10.1001/jamaneurol.2014.193.
• [9] Cognitive characterization of SCAR10 caused by a homozygous c.132dupA mutation in the ANO10 gene.Neurocase. 2019 Oct;25(5):195-201. doi: 10.1080/13554794.2019.1655064. Epub 2019 Aug 19.
• [10] A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25.3 and 3p22.1: a LOC Network study.Neuro Oncol. 2019 Aug 5;21(8):1039-1048. doi: 10.1093/neuonc/noz088.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [15] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [16] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [17] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [18] 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.
• [19] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [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] 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.