Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK8O0X8)

• DOT Name: Myc box-dependent-interacting protein 1 (BIN1)
• Synonyms: Amphiphysin II; Amphiphysin-like protein; Box-dependent myc-interacting protein 1; Bridging integrator 1
• Gene Name: BIN1
• Related Disease:
  Centronuclear myopathy
  Myopathy, centronuclear, 2
  Advanced cancer
  Arrhythmia
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cardiac failure
  Cardiomyopathy
  Colitis
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal carcinoma
  Congenital fiber-type disproportion myopathy
  Congenital structural myopathy
  Congestive heart failure
  Esophageal squamous cell carcinoma
  Hematologic disease
  Liver cancer
  Myocardial infarction
  Myotonic dystrophy
  Primary cutaneous T-cell lymphoma
  Prostate carcinoma
  Prostate neoplasm
  Systemic lupus erythematosus
  Tauopathy
  Temporal lobe epilepsy
  Tubular aggregate myopathy
  Ulcerative colitis
  Myopathy
  Autosomal dominant centronuclear myopathy
  Autosomal recessive centronuclear myopathy
  Non-small-cell lung cancer
  Sezary syndrome
  Breast neoplasm
  Familial Alzheimer disease
  Malignant pleural mesothelioma
  Malignant rhabdoid tumour
  Non-insulin dependent diabetes
  Parkinson disease
  X-linked myotubular myopathy
• UniProt ID: BIN1_HUMAN
• PDB ID: 1MUZ; 1MV0; 1MV3; 2FIC; 2RMY; 2RND; 5I22
• Pfam ID: PF03114 ; PF14604
• Sequence:
  MAEMGSKGVTAGKIASNVQKKLTRAQEKVLQKLGKADETKDEQFEQCVQNFNKQLTEGTR
  LQKDLRTYLASVKAMHEASKKLNECLQEVYEPDWPGRDEANKIAENNDLLWMDYHQKLVD
  QALLTMDTYLGQFPDIKSRIAKRGRKLVDYDSARHHYESLQTAKKKDEAKIAKPVSLLEK
  AAPQWCQGKLQAHLVAQTNLLRNQAEEELIKAQKVFEEMNVDLQEELPSLWNSRVGFYVN
  TFQSIAGLEENFHKEMSKLNQNLNDVLVGLEKQHGSNTFTVKAQPSDNAPAKGNKSPSPP
  DGSPAATPEIRVNHEPEPAGGATPGATLPKSPSQLRKGPPVPPPPKHTPSKEVKQEQILS
  LFEDTFVPEISVTTPSQFEAPGPFSEQASLLDLDFDPLPPVTSPVKAPTPSGQSIPWDLW
  EPTESPAGSLPSGEPSAAEGTFAVSWPSQTAEPGPAQPAEASEVAGGTQPAAGAQEPGET
  AASEAASSSLPAVVVETFPATVNGTVEGGSGAGRLDLPPGFMFKVQAQHDYTATDTDELQ
  LKAGDVVLVIPFQNPEEQDEGWLMGVKESDWNQHKELEKCRGVFPENFTERVP
• Function: Is a key player in the control of plasma membrane curvature, membrane shaping and membrane remodeling. Required in muscle cells for the formation of T-tubules, tubular invaginations of the plasma membrane that function in depolarization-contraction coupling. Is a negative regulator of endocytosis. Is also involved in the regulation of intracellular vesicles sorting, modulation of BACE1 trafficking and the control of amyloid-beta production. In neuronal circuits, endocytosis regulation may influence the internalization of PHF-tau aggregates. May be involved in the regulation of MYC activity and the control cell proliferation. Has actin bundling activity and stabilizes actin filaments against depolymerization in vitro.
• Tissue Specificity: Ubiquitous. Highest expression in the brain and muscle . Expressed in oligodendrocytes . Isoform IIA is expressed only in the brain, where it is detected in the gray matter, but not in the white matter . Isoform BIN1 is widely expressed with highest expression in skeletal muscle.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Fc gamma R-mediated phagocytosis (hsa04666)
• Reactome Pathway: Clathrin-mediated endocytosis (R-HSA-8856828)

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Centronuclear myopathy	DISXBEJO	Definitive	Semidominant	[1]
Myopathy, centronuclear, 2	DIS7NCZX	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Arrhythmia	DISFF2NI	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[6]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Cardiomyopathy	DISUPZRG	Strong	Altered Expression	[7]
Colitis	DISAF7DD	Strong	Biomarker	[8]
Colon cancer	DISVC52G	Strong	Altered Expression	[9]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Congenital fiber-type disproportion myopathy	DISU9T2M	Strong	Biomarker	[11]
Congenital structural myopathy	DISZ9JP4	Strong	Genetic Variation	[11]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Posttranslational Modification	[12]
Hematologic disease	DIS9XD9A	Strong	Biomarker	[13]
Liver cancer	DISDE4BI	Strong	Biomarker	[6]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[14]
Myotonic dystrophy	DISNBEMX	Strong	Biomarker	[15]
Primary cutaneous T-cell lymphoma	DIS35WVW	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[17]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[17]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[18]
Tauopathy	DISY2IPA	Strong	Genetic Variation	[19]
Temporal lobe epilepsy	DISNOPXX	Strong	Biomarker	[20]
Tubular aggregate myopathy	DISC11WH	Strong	Biomarker	[11]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[21]
Myopathy	DISOWG27	moderate	Genetic Variation	[22]
Autosomal dominant centronuclear myopathy	DISF2XWP	Supportive	Autosomal dominant	[23]
Autosomal recessive centronuclear myopathy	DIS4ZI6X	Supportive	Autosomal recessive	[11]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Altered Expression	[3]
Sezary syndrome	DISFMTC7	Disputed	Altered Expression	[16]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[24]
Familial Alzheimer disease	DISE75U4	Limited	Biomarker	[25]
Malignant pleural mesothelioma	DIST2R60	Limited	Altered Expression	[26]
Malignant rhabdoid tumour	DIS46HZU	Limited	Altered Expression	[27]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[28]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[29]
X-linked myotubular myopathy	DISJ95GS	Limited	Genetic Variation	[30]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Myc box-dependent-interacting protein 1 (BIN1) increases the response to substance of Cisplatin.	[49]
Etoposide	DMNH3PG	Approved	Myc box-dependent-interacting protein 1 (BIN1) increases the response to substance of Etoposide.	[49]

1 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 Myc box-dependent-interacting protein 1 (BIN1).	[31]

18 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 Myc box-dependent-interacting protein 1 (BIN1).	[32]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[33]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[36]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[37]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[38]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Myc box-dependent-interacting protein 1 (BIN1).	[39]
Selenium	DM25CGV	Approved	Selenium increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[40]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[41]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[42]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[43]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[44]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[40]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[45]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[46]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Myc box-dependent-interacting protein 1 (BIN1).	[47]
Paraquat	DMR8O3X	Investigative	Paraquat affects the splicing of Myc box-dependent-interacting protein 1 (BIN1).	[48]

References

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• [2] Phenotype of a patient with recessive centronuclear myopathy and a novel BIN1 mutation. Neurology. 2010 Feb 9;74(6):519-21. doi: 10.1212/WNL.0b013e3181cef7f9.
• [3] SRSF1-dependent alternative splicing attenuates BIN1 expression in non-small cell lung cancer.J Cell Biochem. 2020 Feb;121(2):946-953. doi: 10.1002/jcb.29366. Epub 2019 Sep 3.
• [4] Effect of BIN1 on cardiac dysfunction and malignant arrhythmias.Acta Physiol (Oxf). 2020 Mar;228(3):e13429. doi: 10.1111/apha.13429. Epub 2019 Dec 26.
• [5] Losses of the tumor suppressor BIN1 in breast carcinoma are frequent and reflect deficits in programmed cell death capacity.Int J Cancer. 2000 Feb 1;85(3):376-83.
• [6] Splicing Regulator p54(nrb) /Non-POU Domain-Containing Octamer-Binding Protein Enhances Carcinogenesis Through Oncogenic Isoform Switch of MYC Box-Dependent Interacting Protein 1 in Hepatocellular Carcinoma.Hepatology. 2020 Aug;72(2):548-568. doi: 10.1002/hep.31062. Epub 2020 Mar 25.
• [7] Cardiac BIN1 (cBIN1) is a regulator of cardiac contractile function and an emerging biomarker of heart muscle health.Sci China Life Sci. 2017 Mar;60(3):257-263. doi: 10.1007/s11427-016-0249-x. Epub 2016 Nov 23.
• [8] Novel Colitis Immunotherapy Targets Bin1 and Improves Colon Cell Barrier Function.Dig Dis Sci. 2016 Feb;61(2):423-32. doi: 10.1007/s10620-015-3804-8. Epub 2015 Jul 21.
• [9] The paradoxical patterns of expression of indoleamine 2,3-dioxygenase in colon cancer.J Transl Med. 2009 Aug 20;7:71. doi: 10.1186/1479-5876-7-71.
• [10] Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer.Cancer Res. 2007 Aug 15;67(16):7605-12. doi: 10.1158/0008-5472.CAN-07-1100.
• [11] Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. Nat Genet. 2007 Sep;39(9):1134-9. doi: 10.1038/ng2086. Epub 2007 Aug 5.
• [12] Methylation decreases the Bin1 tumor suppressor in ESCC and restoration by decitabine inhibits the epithelial mesenchymal transition.Oncotarget. 2017 Mar 21;8(12):19661-19673. doi: 10.18632/oncotarget.14914.
• [13] Inverse regulation of bridging integrator 1 and BCR-ABL1 in chronic myeloid leukemia.Tumour Biol. 2016 Jan;37(1):217-25. doi: 10.1007/s13277-015-3772-9. Epub 2015 Jul 21.
• [14] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [15] N-WASP is required for Amphiphysin-2/BIN1-dependent nuclear positioning and triad organization in skeletal muscle and is involved in the pathophysiology of centronuclear myopathy.EMBO Mol Med. 2014 Nov;6(11):1455-75. doi: 10.15252/emmm.201404436.
• [16] BIN1 tumor suppressor regulates Fas/Fas ligand-mediated apoptosis through c-FLIP in cutaneous T-cell lymphoma.Leukemia. 2015 Jun;29(6):1402-13. doi: 10.1038/leu.2015.9. Epub 2015 Jan 12.
• [17] Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma.Int J Cancer. 2000 Apr 15;86(2):155-61. doi: 10.1002/(sici)1097-0215(20000415)86:2<155::aid-ijc2>3.0.co;2-m.
• [18] GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.Genes Immun. 2014 Sep;15(6):347-54. doi: 10.1038/gene.2014.23. Epub 2014 May 29.
• [19] Structural Basis of Tau Interaction With BIN1 and Regulation by Tau Phosphorylation.Front Mol Neurosci. 2018 Nov 14;11:421. doi: 10.3389/fnmol.2018.00421. eCollection 2018.
• [20] Gene expression variance in hippocampal tissue of temporal lobe epilepsy patients corresponds to differential memory performance.Neurobiol Dis. 2016 Feb;86:121-30. doi: 10.1016/j.nbd.2015.11.011. Epub 2015 Nov 26.
• [21] Intestinal barrier tightening by a cell-penetrating antibody to Bin1, a candidate target for immunotherapy of ulcerative colitis.J Cell Biochem. 2019 Mar;120(3):4225-4237. doi: 10.1002/jcb.27716. Epub 2018 Sep 30.
• [22] Trouble at the junction: When myopathy and myasthenia overlap.Muscle Nerve. 2019 Dec;60(6):648-657. doi: 10.1002/mus.26676. Epub 2019 Sep 10.
• [23] Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations. Brain. 2014 Dec;137(Pt 12):3160-70. doi: 10.1093/brain/awu272. Epub 2014 Sep 25.
• [24] Bin1 attenuation in breast cancer is correlated to nodal metastasis and reduced survival.Cancer Biol Ther. 2007 Feb;6(2):192-4. doi: 10.4161/cbt.6.2.3587. Epub 2007 Feb 7.
• [25] BIN1 is decreased in sporadic but not familial Alzheimer's disease or in aging.PLoS One. 2013 Oct 21;8(10):e78806. doi: 10.1371/journal.pone.0078806. eCollection 2013.
• [26] High BIN1 expression has a favorable prognosis in malignant pleural mesothelioma and is associated with tumor infiltrating lymphocytes.Lung Cancer. 2019 Apr;130:35-41. doi: 10.1016/j.lungcan.2019.02.005. Epub 2019 Feb 7.
• [27] Epigenetic inactivation of the tumor suppressor BIN1 drives proliferation of SNF5-deficient tumors.Cell Cycle. 2012 May 15;11(10):1956-65. doi: 10.4161/cc.20280. Epub 2012 May 15.
• [28] Potential contribution of the Alzheimer's disease risk locus BIN1 to episodic memory performance in cognitively normal Type 2 diabetes elderly.Eur Neuropsychopharmacol. 2016 Apr;26(4):787-95. doi: 10.1016/j.euroneuro.2015.11.004. Epub 2015 Nov 14.
• [29] The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease.J Neurol. 2015 Nov;262(11):2443-7. doi: 10.1007/s00415-015-7868-3. Epub 2015 Aug 2.
• [30] "Necklace" fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy.Acta Neuropathol. 2009 Mar;117(3):283-91. doi: 10.1007/s00401-008-0472-1. Epub 2008 Dec 16.
• [31] 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.
• [32] 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.
• [33] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [34] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [35] 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.
• [36] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [37] 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.
• [38] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [39] 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.
• [40] 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.
• [41] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [42] Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. Leuk Res. 2008 Feb;32(2):275-85. doi: 10.1016/j.leukres.2007.05.024. Epub 2007 Jul 19.
• [43] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [44] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [45] 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.
• [46] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [47] 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.
• [48] Paraquat modulates alternative pre-mRNA splicing by modifying the intracellular distribution of SRPK2. PLoS One. 2013 Apr 16;8(4):e61980. doi: 10.1371/journal.pone.0061980. Print 2013.
• [49] c-MYC suppresses BIN1 to release poly(ADP-ribose) polymerase 1: a mechanism by which cancer cells acquire cisplatin resistance. Sci Signal. 2011 Mar 29;4(166):ra19. doi: 10.1126/scisignal.2001556.