Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6UABPM)

• DOT Name: Band 4.1-like protein 2 (EPB41L2)
• Synonyms: Erythrocyte membrane protein band 4.1-like 2; Generally expressed protein 4.1; 4.1G
• Gene Name: EPB41L2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Urolithiasis
• UniProt ID: E41L2_HUMAN
• Pfam ID: PF05902 ; PF08736 ; PF09380 ; PF00373 ; PF09379 ; PF04382
• Sequence:
  MTTEVGSVSEVKKDSSQLGTDATKEKPKEVAENQQNQSSDPEEEKGSQPPPAAESQSSLR
  RQKREKETSESRGISRFIPPWLKKQKSYTLVVAKDGGDKKEPTQAVVEEQVLDKEEPLPE
  EQRQAKGDAEEMAQKKQEIKVEVKEEKPSVSKEEKPSVSKVEMQPTELVSKEREEKVKET
  QEDKLEGGAAKRETKEVQTNELKAEKASQKVTKKTKTVQCKVTLLDGTEYSCDLEKHAKG
  QVLFDKVCEHLNLLEKDYFGLLFQESPEQKNWLDPAKEIKRQLRNLPWLFTFNVKFYPPD
  PSQLTEDITRYFLCLQLRQDIASGRLPCSFVTHALLGSYTLQAELGDYDPEEHGSIDLSE
  FQFAPTQTKELEEKVAELHKTHRGLSPAQADSQFLENAKRLSMYGVDLHHAKDSEGVDIK
  LGVCANGLLIYKDRLRINRFAWPKILKISYKRSNFYIKVRPAELEQFESTIGFKLPNHRA
  AKRLWKVCVEHHTFYRLVSPEQPPKAKFLTLGSKFRYSGRTQAQTRQASTLIDRPAPHFE
  RTSSKRVSRSLDGAPIGVMDQSLMKDFPGAAGEISAYGPGLVSIAVVQDGDGRREVRSPT
  KAPHLQLIEGKKNSLRVEGDNIYVRHSNLMLEELDKAQEDILKHQASISELKRNFMESTP
  EPRPNEWEKRRITPLSLQTQGSSHETLNIVEEKKRAEVGKDERVITEEMNGKEISPGSGP
  GEIRKVEPVTQKDSTSLSSESSSSSSESEEEDVGEYRPHHRVTEGTIREEQEYEEEVEEE
  PRPAAKVVEREEAVPEASPVTQAGASVITVETVIQENVGAQKIPGEKSVHEGALKQDMGE
  EAEEEPQKVNGEVSHVDIDVLPQIICCSEPPVVKTEMVTISDASQRTEISTKEVPIVQTE
  TKTITYESPQIDGGAGGDSGTLLTAQTITSESVSTTTTTHITKTVKGGISETRIEKRIVI
  TGDGDIDHDQALAQAIREAREQHPDMSVTRVVVHKETELAEEGED
• Function: Required for dynein-dynactin complex and NUMA1 recruitment at the mitotic cell cortex during anaphase.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Urolithiasis	DISNFTKT	moderate	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Band 4.1-like protein 2 (EPB41L2) affects the response to substance of Mitoxantrone.	[25]

21 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 2 (EPB41L2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Band 4.1-like protein 2 (EPB41L2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Band 4.1-like protein 2 (EPB41L2).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Band 4.1-like protein 2 (EPB41L2).	[13]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[15]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Band 4.1-like protein 2 (EPB41L2).	[16]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Band 4.1-like protein 2 (EPB41L2).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Band 4.1-like protein 2 (EPB41L2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Band 4.1-like protein 2 (EPB41L2).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Band 4.1-like protein 2 (EPB41L2).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Band 4.1-like protein 2 (EPB41L2).	[23]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Band 4.1-like protein 2 (EPB41L2).	[24]

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 decreases the methylation of Band 4.1-like protein 2 (EPB41L2).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Band 4.1-like protein 2 (EPB41L2).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Band 4.1-like protein 2 (EPB41L2).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Band 4.1-like protein 2 (EPB41L2).	[21]

References

• [1] Expression of Protein 4.1 Family in Breast Cancer: Database Mining for 4.1 Family Members in Malignancies.Med Sci Monit. 2019 May 7;25:3374-3389. doi: 10.12659/MSM.914085.
• [2] Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.J Am Soc Nephrol. 2019 May;30(5):855-864. doi: 10.1681/ASN.2018090942. Epub 2019 Apr 11.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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.
• [10] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [11] 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.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [14] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [15] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [16] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [17] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [18] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [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] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [21] 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.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] Alteration of estrogen-regulated gene expression in human cells induced by the agricultural and horticultural herbicide glyphosate. Hum Exp Toxicol. 2007 Sep;26(9):747-52. doi: 10.1177/0960327107083453.
• [25] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.