Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4CL5DC)

• DOT Name: Band 4.1-like protein 1 (EPB41L1)
• Synonyms: Erythrocyte membrane protein band 4.1-like 1; Neuronal protein 4.1; 4.1N
• Gene Name: EPB41L1
• Related Disease:
  Schizophrenia
  Autosomal dominant non-syndromic intellectual disability
  Complex neurodevelopmental disorder
  Intellectual disability
  Intellectual disability, autosomal dominant 40
• UniProt ID: E41L1_HUMAN
• Pfam ID: PF05902 ; PF08736 ; PF09380 ; PF00373 ; PF09379 ; PF04382
• Sequence:
  MTTETGPDSEVKKAQEEAPQQPEAAAAVTTPVTPAGHGHPEANSNEKHPSQQDTRPAEQS
  LDMEEKDYSEADGLSERTTPSKAQKSPQKIAKKYKSAICRVTLLDASEYECEVEKHGRGQ
  VLFDLVCEHLNLLEKDYFGLTFCDADSQKNWLDPSKEIKKQIRSSPWNFAFTVKFYPPDP
  AQLTEDITRYYLCLQLRADIITGRLPCSFVTHALLGSYAVQAELGDYDAEEHVGNYVSEL
  RFAPNQTRELEERIMELHKTYRGMTPGEAEIHFLENAKKLSMYGVDLHHAKDSEGIDIML
  GVCANGLLIYRDRLRINRFAWPKILKISYKRSNFYIKIRPGEYEQFESTIGFKLPNHRSA
  KRLWKVCIEHHTFFRLVSPEPPPKGFLVMGSKFRYSGRTQAQTRQASALIDRPAPFFERS
  SSKRYTMSRSLDGAEFSRPASVSENHDAGPDGDKRDEDGESGGQRSEAEEGEVRTPTKIK
  ELKPEQETTPRHKQEFLDKPEDVLLKHQASINELKRTLKEPNSKLIHRDRDWERERRLPS
  SPASPSPKGTPEKANERAGLREGSEEKVKPPRPRAPESDTGDEDQDQERDTVFLKDNHLA
  IERKCSSITVSSTSSLEAEVDFTVIGDYHGSAFEDFSRSLPELDRDKSDSDTEGLLFSRD
  LNKGAPSQDDESGGIEDSPDRGACSTPDMPQFEPVKTETMTVSSLAIRKKIEPEAVLQTR
  VSAMDNTQQVDGSASVGREFIATTPSITTETISTTMENSLKSGKGAAAMIPGPQTVATEI
  RSLSPIIGKDVLTSTYGATAETLSTSTTTHVTKTVKGGFSETRIEKRIIITGDEDVDQDQ
  ALALAIKEAKLQHPDMLVTKAVVYRETDPSPEERDKKPQES
• Function: May function to confer stability and plasticity to neuronal membrane via multiple interactions, including the spectrin-actin-based cytoskeleton, integral membrane channels and membrane-associated guanylate kinases.
• Tissue Specificity: Highest expression in brain, lower in heart, kidney, pancreas, placenta, lung and skeletal muscle.
• Reactome Pathway:
  Neurexins and neuroligins (R-HSA-6794361)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  Trafficking of AMPA receptors (R-HSA-399719)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Altered Expression	[1]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[2]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[3]
Intellectual disability	DISMBNXP	Limited	Biomarker	[2]
Intellectual disability, autosomal dominant 40	DISAI0IH	Limited	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Band 4.1-like protein 1 (EPB41L1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Band 4.1-like protein 1 (EPB41L1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Band 4.1-like protein 1 (EPB41L1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Band 4.1-like protein 1 (EPB41L1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Band 4.1-like protein 1 (EPB41L1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Band 4.1-like protein 1 (EPB41L1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Band 4.1-like protein 1 (EPB41L1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Band 4.1-like protein 1 (EPB41L1).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Band 4.1-like protein 1 (EPB41L1).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Band 4.1-like protein 1 (EPB41L1).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Band 4.1-like protein 1 (EPB41L1).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Band 4.1-like protein 1 (EPB41L1).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Band 4.1-like protein 1 (EPB41L1).	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Band 4.1-like protein 1 (EPB41L1).	[19]

4 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 Band 4.1-like protein 1 (EPB41L1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Band 4.1-like protein 1 (EPB41L1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Band 4.1-like protein 1 (EPB41L1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Band 4.1-like protein 1 (EPB41L1).	[16]

References

• [1] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [2] Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011 Mar 11;88(3):306-16. doi: 10.1016/j.ajhg.2011.02.001. Epub 2011 Mar 3.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] 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.
• [12] Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat Commun. 2018 Aug 9;9(1):3069. doi: 10.1038/s41467-018-05402-2.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.