Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMTP2Z7)

• DOT Name: Microtubule-associated protein tau (MAPT)
• Synonyms: Neurofibrillary tangle protein; Paired helical filament-tau; PHF-tau
• Gene Name: MAPT
• Related Disease:
  Late-onset Parkinson disease
  Pick disease
  Semantic dementia
  Supranuclear palsy, progressive, 1
  Progressive supranuclear palsy-parkinsonism syndrome
• UniProt ID: TAU_HUMAN
• PDB ID: 1I8H ; 2MZ7 ; 2ON9 ; 3OVL ; 4E0M ; 4E0N ; 4E0O ; 4FL5 ; 4GLR ; 4NP8 ; 4TQE ; 4Y32 ; 4Y3B ; 4Y5I ; 5DMG ; 5E2V ; 5E2W ; 5HF3 ; 5K7N ; 5MO3 ; 5MP1 ; 5MP3 ; 5MP5 ; 5N5A ; 5N5B ; 5NVB ; 5O3L ; 5O3O ; 5O3T ; 5V5B ; 5V5C ; 5ZIA ; 5ZV3 ; 6BB4 ; 6CVJ ; 6CVN ; 6DC8 ; 6DC9 ; 6DCA ; 6FBW ; 6FI5 ; 6GK7 ; 6GK8 ; 6GX5 ; 6H06 ; 6HRE ; 6HRF ; 6LRA ; 6N4P ; 6NK4 ; 6NWP ; 6NWQ ; 6ODG ; 6PXR ; 6QJH ; 6QJM ; 6QJP ; 6QJQ ; 6TJO ; 6TJX ; 6VH7 ; 6VHA ; 6VHL ; 6VI3 ; 6XLI ; 7EYC ; 7KQK ; 7MKF ; 7MKG ; 7MKH ; 7NRQ ; 7NRS ; 7NRT ; 7NRV ; 7NRX ; 7P65 ; 7P66 ; 7P67 ; 7P68 ; 7P6A ; 7P6B ; 7P6C ; 7P6D ; 7P6E ; 7PQC ; 7PQP ; 7QJV ; 7QJW ; 7QJX ; 7QJY ; 7QJZ ; 7QK1 ; 7QK2 ; 7QK3 ; 7QK5 ; 7QK6 ; 7QKF ; 7QKG ; 7QKH ; 7QKI ; 7QKJ ; 7QKK ; 7QKL ; 7QKM ; 7QKU ; 7QKV ; 7QKW ; 7QKX ; 7QKY ; 7QKZ ; 7QL0 ; 7QL1 ; 7QL2 ; 7QL3 ; 7QL4 ; 7R4T ; 7R5H ; 7SP1 ; 7U0Z ; 7UPE ; 7UPF ; 7UPG ; 7YMN ; 7YPG ; 8AZU ; 8BGS ; 8BGV ; 8BYN ; 8CAQ ; 8CAX ; 8FNZ ; 8FUG ; 8G54 ; 8G55 ; 8G58 ; 8OP0 ; 8OPI ; 8ORE ; 8ORF ; 8ORG ; 8P34 ; 8PII ; 8PPO ; 8Q27 ; 8Q2J ; 8Q2K ; 8Q2L ; 8Q7F ; 8Q7L ; 8Q7M ; 8Q7P ; 8Q7T ; 8Q88 ; 8Q8C ; 8Q8D ; 8Q8E ; 8Q8F ; 8Q8L ; 8Q8M ; 8Q8R ; 8Q8S ; 8Q8U ; 8Q8V ; 8Q8W ; 8Q8X ; 8Q8Y ; 8Q8Z ; 8Q92 ; 8Q97 ; 8Q98 ; 8Q99 ; 8Q9A ; 8Q9B ; 8Q9C ; 8Q9D ; 8Q9E ; 8Q9F ; 8Q9G ; 8Q9H ; 8Q9I ; 8Q9J ; 8Q9K ; 8Q9L ; 8Q9M ; 8Q9O ; 8QCP ; 8QCR ; 8QJJ ; 8R3T
• Pfam ID: PF00418
• Sequence:
  MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPG
  SETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAG
  HVTQEPESGKVVQEGFLREPGPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEG
  GRHAPELLKHQLLGDLHQEGPPLKGAGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPA
  QDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIPASEPDGPSVGRAKGQDAPLE
  FTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEADLPEPSEKQPA
  AAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPCLSPKHPTPGSS
  DPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQK
  GQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREP
  KKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLD
  LSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEK
  LDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDT
  SPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL
• Function: Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity. The C-terminus binds axonal microtubules while the N-terminus binds neural plasma membrane components, suggesting that tau functions as a linker protein between both. Axonal polarity is predetermined by TAU/MAPT localization (in the neuronal cell) in the domain of the cell body defined by the centrosome. The short isoforms allow plasticity of the cytoskeleton whereas the longer isoforms may preferentially play a role in its stabilization.
• Tissue Specificity: Expressed in neurons. Isoform PNS-tau is expressed in the peripheral nervous system while the others are expressed in the central nervous system.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  (Name not found)
  Caspase-mediated cleavage of cytoskeletal proteins (R-HSA-264870)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Late-onset Parkinson disease	DIS9IOUI	Strong	Autosomal dominant	[1]
Pick disease	DISP6X50	Strong	Autosomal dominant	[1]
Semantic dementia	DISA7775	Strong	Autosomal dominant	[1]
Supranuclear palsy, progressive, 1	DIS47BVM	Strong	Autosomal dominant	[1]
Progressive supranuclear palsy-parkinsonism syndrome	DISEARF8	Moderate	Autosomal recessive	[1]

12 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 Microtubule-associated protein tau (MAPT).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Microtubule-associated protein tau (MAPT).	[8]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the phosphorylation of Microtubule-associated protein tau (MAPT).	[18]
G1	DMTV42K	Phase 1/2	G1 affects the phosphorylation of Microtubule-associated protein tau (MAPT).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Microtubule-associated protein tau (MAPT).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Microtubule-associated protein tau (MAPT).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Microtubule-associated protein tau (MAPT).	[27]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the phosphorylation of Microtubule-associated protein tau (MAPT).	[33]
acrolein	DMAMCSR	Investigative	acrolein increases the phosphorylation of Microtubule-associated protein tau (MAPT).	[34]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the phosphorylation of Microtubule-associated protein tau (MAPT).	[34]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the phosphorylation of Microtubule-associated protein tau (MAPT).	[35]
Cordycepin	DM72Y01	Investigative	Cordycepin increases the phosphorylation of Microtubule-associated protein tau (MAPT).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Microtubule-associated protein tau (MAPT).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Microtubule-associated protein tau (MAPT).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Microtubule-associated protein tau (MAPT).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Microtubule-associated protein tau (MAPT).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Microtubule-associated protein tau (MAPT).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Microtubule-associated protein tau (MAPT).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Microtubule-associated protein tau (MAPT).	[11]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Microtubule-associated protein tau (MAPT).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Microtubule-associated protein tau (MAPT).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Microtubule-associated protein tau (MAPT).	[14]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Microtubule-associated protein tau (MAPT).	[15]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Simvastatin	DM30SGU	Approved	Simvastatin affects the expression of Microtubule-associated protein tau (MAPT).	[16]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Microtubule-associated protein tau (MAPT).	[17]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Mebendazole	DMO14SG	Approved	Mebendazole decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Emetine	DMCT2YF	Approved	Emetine decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Norethindrone	DMTY169	Approved	Norethindrone decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Albendazole	DMYZ57N	Approved	Albendazole decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Methylene blue	DMJAPE7	Approved	Methylene blue increases the expression of Microtubule-associated protein tau (MAPT).	[5]
Ciclopirox	DMN5T2A	Approved	Ciclopirox decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Podofilox	DMT2EJP	Approved	Podofilox decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Microtubule-associated protein tau (MAPT).	[20]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Microtubule-associated protein tau (MAPT).	[21]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of Microtubule-associated protein tau (MAPT).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Microtubule-associated protein tau (MAPT).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Microtubule-associated protein tau (MAPT).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Microtubule-associated protein tau (MAPT).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Microtubule-associated protein tau (MAPT).	[26]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of Microtubule-associated protein tau (MAPT).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Microtubule-associated protein tau (MAPT).	[30]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Microtubule-associated protein tau (MAPT).	[31]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Microtubule-associated protein tau (MAPT).	[32]
tryptanthrin	DMTRYCI	Investigative	tryptanthrin increases the expression of Microtubule-associated protein tau (MAPT).	[37]
8-Azaguanine	DM7VP90	Investigative	8-Azaguanine decreases the expression of Microtubule-associated protein tau (MAPT).	[5]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Lansoprazole	DMXYLQ3	Approved	Lansoprazole affects the binding of Microtubule-associated protein tau (MAPT).	[19]
Astemizole	DM2HN6Q	Withdrawn from market	Astemizole affects the binding of Microtubule-associated protein tau (MAPT).	[19]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [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] 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.
• [4] 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.
• [5] Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression. Mol Neurodegener. 2006 Jul 26;1:6. doi: 10.1186/1750-1326-1-6.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] 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.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Neuroprotective effects of glucomoringin-isothiocyanate against H(2)O(2)-Induced cytotoxicity in neuroblastoma (SH-SY5Y) cells. Neurotoxicology. 2019 Dec;75:89-104. doi: 10.1016/j.neuro.2019.09.008. Epub 2019 Sep 12.
• [10] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [11] The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells. Breast Cancer Res. 2010;12(3):R43. doi: 10.1186/bcr2598. Epub 2010 Jun 28.
• [12] 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.
• [13] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [14] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [15] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [16] Differential effects of simvastatin and pravastatin on expression of Alzheimer's disease-related genes in human astrocytes and neuronal cells. J Lipid Res. 2009 Oct;50(10):2095-102. doi: 10.1194/jlr.M900236-JLR200. Epub 2009 May 21.
• [17] Capsaicin inhibits the migration, invasion and EMT of renal cancer cells by inducing AMPK/mTOR-mediated autophagy. Chem Biol Interact. 2022 Oct 1;366:110043. doi: 10.1016/j.cbi.2022.110043. Epub 2022 Aug 28.
• [18] CDK5-mediated tau accumulation triggers methamphetamine-induced neuronal apoptosis via endoplasmic reticulum-associated degradation pathway. Toxicol Lett. 2018 Aug;292:97-107. doi: 10.1016/j.toxlet.2018.04.027. Epub 2018 Apr 26.
• [19] Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease. J Alzheimers Dis. 2010;19(2):573-89. doi: 10.3233/JAD-2010-1262.
• [20] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [21] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [22] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [23] Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
• [24] 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.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [27] 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.
• [28] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [29] 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.
• [30] 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.
• [31] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [32] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [33] Neurotoxicity induced by okadaic acid in the human neuroblastoma SH-SY5Y line can be differentially prevented by 7 and 2* nicotinic stimulation. Toxicol Sci. 2011 Sep;123(1):193-205. doi: 10.1093/toxsci/kfr163. Epub 2011 Jun 29.
• [34] Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells. J Neurosci Res. 2003 Mar 15;71(6):863-70. doi: 10.1002/jnr.10525.
• [35] Alterations of tau and VASP during microcystin-LR-induced cytoskeletal reorganization in a human liver cell line. Environ Toxicol. 2015 Jan;30(1):92-100. doi: 10.1002/tox.21898. Epub 2013 Aug 9.
• [36] Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes. Neurobiol Dis. 2021 Jan;147:105148. doi: 10.1016/j.nbd.2020.105148. Epub 2020 Oct 25.
• [37] Tryptanthrin induces growth inhibition and neuronal differentiation in the human neuroblastoma LA-N-1 cells. Chem Biol Interact. 2013 Apr 25;203(2):512-21. doi: 10.1016/j.cbi.2013.03.001. Epub 2013 Mar 13.