Details of Drug Off-Target (DOT)

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

• DOT Name: Anoctamin-1 (ANO1)
• Synonyms: Discovered on gastrointestinal stromal tumors protein 1; Oral cancer overexpressed protein 2; Transmembrane protein 16A; Tumor-amplified and overexpressed sequence 2
• Gene Name: ANO1
• Related Disease: Intestinal dysmotility syndrome
• UniProt ID: ANO1_HUMAN
• Pfam ID: PF16178 ; PF04547
• Sequence:
  MRVNEKYSTLPAEDRSVHIINICAIEDIGYLPSEGTLLNSLSVDPDAECKYGLYFRDGRR
  KVDYILVYHHKRPSGNRTLVRRVQHSDTPSGARSVKQDHPLPGKGASLDAGSGEPPMDYH
  EDDKRFRREEYEGNLLEAGLELERDEDTKIHGVGFVKIHAPWNVLCREAEFLKLKMPTKK
  MYHINETRGLLKKINSVLQKITDPIQPKVAEHRPQTMKRLSYPFSREKQHLFDLSDKDSF
  FDSKTRSTIVYEILKRTTCTKAKYSMGITSLLANGVYAAAYPLHDGDYNGENVEFNDRKL
  LYEEWARYGVFYKYQPIDLVRKYFGEKIGLYFAWLGVYTQMLIPASIVGIIVFLYGCATM
  DENIPSMEMCDQRHNITMCPLCDKTCSYWKMSSACATARASHLFDNPATVFFSVFMALWA
  ATFMEHWKRKQMRLNYRWDLTGFEEEEEAVKDHPRAEYEARVLEKSLKKESRNKEKRRHI
  PEESTNKWKQRVKTAMAGVKLTDKVKLTWRDRFPAYLTNLVSIIFMIAVTFAIVLGVIIY
  RISMAAALAMNSSPSVRSNIRVTVTATAVIINLVVIILLDEVYGCIARWLTKIEVPKTEK
  SFEERLIFKAFLLKFVNSYTPIFYVAFFKGRFVGRPGDYVYIFRSFRMEECAPGGCLMEL
  CIQLSIIMLGKQLIQNNLFEIGIPKMKKLIRYLKLKQQSPPDHEECVKRKQRYEVDYNLE
  PFAGLTPEYMEMIIQFGFVTLFVASFPLAPLFALLNNIIEIRLDAKKFVTELRRPVAVRA
  KDIGIWYNILRGIGKLAVIINAFVISFTSDFIPRLVYLYMYSKNGTMHGFVNHTLSSFNV
  SDFQNGTAPNDPLDLGYEVQICRYKDYREPPWSENKYDISKDFWAVLAARLAFVIVFQNL
  VMFMSDFVDWVIPDIPKDISQQIHKEKVLMVELFMREEQDKQQLLETWMEKERQKDEPPC
  NHHNTKACPDSLGSPAPSHAYHGGVL
• Function: Calcium-activated chloride channel (CaCC). Plays a role in transepithelial anion transport and smooth muscle contraction. Required for the normal functioning of the interstitial cells of Cajal (ICCs) which generate electrical pacemaker activity in gastrointestinal smooth muscles. Acts as a major contributor to basal and stimulated chloride conductance in airway epithelial cells and plays an important role in tracheal cartilage development. Required for CFTR activation by enhancing endoplasmic reticulum Ca(2+) store release and is also required for CFTR membrane expression. Required for basal and ATP-dependent mucus secretion in airways and intestine, probably by controlling exocytosis of mucus-filled granules by providing Ca(2+) to an apical signaling compartment. Contributes to airway mucus expression induced by interleukins IL3 and IL8 and by the asthma-associated protein CLCA1 and is required for expression of mucin MUC5AC. However, was shown in another study not to be required for MUC5AC expression. Plays a role in the propagation of Ca(2+) waves in Kolliker's organ in the cochlea and contributes to the refinement of auditory brainstem circuitries prior to hearing onset. In vomeronasal sensory neurons, modulates spontaneous firing patterns in the absence of stimuli as well as the firing pattern of pheromone-evoked activity. Responsible for calcium-activated chloride channel activity in type I taste cells of the vallate papillae. Acts as a heat sensor in nociceptive neurons. In dorsal root ganglion neurons, plays a role in mediating non-histaminergic Mas-related G-protein coupled receptor (MRGPR)-dependent itching, acting as a downstream effector of MRGPRs. In the developing brain, required for the Ca(2+)-dependent process extension of radial glial cells; [Isoform 4]: Calcium-activated chloride channel (CaCC). Contributes to calcium-activated chloride secretion in human sweat gland epithelial cells. Shows increased basal chloride permeability and decreased Ca(2+)-induced chloride permeability; [Isoform 5]: Calcium-activated chloride channel (CaCC). Shows increased sensitivity to intracellular Ca(2+).
• Tissue Specificity: Expressed in nasal epithelial cells (at protein level) . In the kidney, expressed in the collecting duct (at protein level) . Broadly expressed with higher levels in liver, skeletal muscle and gastrointestinal muscles . Expressed in eccrine sweat glands .
• Reactome Pathway:
  Induction of Cell-Cell Fusion (R-HSA-9733458)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intestinal dysmotility syndrome	DISENZKO	Limited	Autosomal recessive	[1]

4 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 Anoctamin-1 (ANO1).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Anoctamin-1 (ANO1).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Anoctamin-1 (ANO1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Anoctamin-1 (ANO1).	[16]

15 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-1 (ANO1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Anoctamin-1 (ANO1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Anoctamin-1 (ANO1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Anoctamin-1 (ANO1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Anoctamin-1 (ANO1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Anoctamin-1 (ANO1).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Anoctamin-1 (ANO1).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Anoctamin-1 (ANO1).	[12]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Anoctamin-1 (ANO1).	[13]
Nimodipine	DMQ0RKZ	Approved	Nimodipine decreases the activity of Anoctamin-1 (ANO1).	[14]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Anoctamin-1 (ANO1).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Anoctamin-1 (ANO1).	[12]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Anoctamin-1 (ANO1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Anoctamin-1 (ANO1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Anoctamin-1 (ANO1).	[12]

References

• [1] TMEM16A deficiency: a potentially fatal neonatal disease resulting from impaired chloride currents. J Med Genet. 2021 Apr;58(4):247-253. doi: 10.1136/jmedgenet-2020-106978. Epub 2020 Jun 2.
• [2] 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.
• [3] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [4] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] 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.
• [11] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [12] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [13] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [14] Nimodipine inhibits intestinal and aortic smooth muscle contraction by regulating Ca(2+)-activated Cl(-) channels. Toxicol Appl Pharmacol. 2021 Jun 15;421:115543. doi: 10.1016/j.taap.2021.115543. Epub 2021 Apr 16.
• [15] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [16] 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.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.