Details of Drug Off-Target (DOT)

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

• DOT Name: TAR DNA-binding protein 43 (TARDBP)
• Synonyms: TDP-43
• Gene Name: TARDBP
• Related Disease:
  Amyotrophic lateral sclerosis type 10
  Amyotrophic lateral sclerosis
  Frontotemporal dementia with motor neuron disease
• UniProt ID: TADBP_HUMAN
• PDB ID: 1WF0 ; 2CQG ; 2N2C ; 2N3X ; 2N4G ; 2N4H ; 2N4P ; 4BS2 ; 4IUF ; 4Y00 ; 4Y0F ; 5MDI ; 5MRG ; 5W50 ; 5W52 ; 5W7V ; 5WHN ; 5WHP ; 5WIA ; 5WIQ ; 5WKB ; 5WKD ; 5X4F ; 6B1G ; 6CF4 ; 6CFH ; 6N37 ; 6N3A ; 6N3B ; 6N3C ; 6T4B ; 7KWZ ; 7N9H ; 7PY2 ; 7Q3U ; 8A6I ; 8CG3 ; 8CGG ; 8CGH
• Pfam ID: PF00076 ; PF20910 ; PF18694
• Sequence:
  MSEYIRVTEDENDEPIEIPSEDDGTVLLSTVTAQFPGACGLRYRNPVSQCMRGVRLVEGI
  LHAPDAGWGNLVYVVNYPKDNKRKMDETDASSAVKVKRAVQKTSDLIVLGLPWKTTEQDL
  KEYFSTFGEVLMVQVKKDLKTGHSKGFGFVRFTEYETQVKVMSQRHMIDGRWCDCKLPNS
  KQSQDEPLRSRKVFVGRCTEDMTEDELREFFSQYGDVMDVFIPKPFRAFAFVTFADDQIA
  QSLCGEDLIIKGISVHISNAEPKHNSNRQLERSGRFGGNPGGFGNQGGFGNSRGGGAGLG
  NNQGSNMGGGMNFGAFSINPAMMAAAQAALQSSWGMMGMLASQQNQSGPSGNNQNQGNMQ
  REPNQAFGSGNNSYSGSNSGAAIGWGSASNAGSGSGFNGGFGSSMDSKSSGWGM
• Function: RNA-binding protein that is involved in various steps of RNA biogenesis and processing. Preferentially binds, via its two RNA recognition motifs RRM1 and RRM2, to GU-repeats on RNA molecules predominantly localized within long introns and in the 3'UTR of mRNAs. In turn, regulates the splicing of many non-coding and protein-coding RNAs including proteins involved in neuronal survival, as well as mRNAs that encode proteins relevant for neurodegenerative diseases. Plays a role in maintaining mitochondrial homeostasis by regulating the processing of mitochondrial transcripts. Regulates also mRNA stability by recruiting CNOT7/CAF1 deadenylase on mRNA 3'UTR leading to poly(A) tail deadenylation and thus shortening. In response to oxidative insult, associates with stalled ribosomes localized to stress granules (SGs) and contributes to cell survival. Participates also in the normal skeletal muscle formation and regeneration, forming cytoplasmic myo-granules and binding mRNAs that encode sarcomeric proteins. Plays a role in the maintenance of the circadian clock periodicity via stabilization of the CRY1 and CRY2 proteins in a FBXL3-dependent manner. Negatively regulates the expression of CDK6. Regulates the expression of HDAC6, ATG7 and VCP in a PPIA/CYPA-dependent manner.
• Tissue Specificity: Ubiquitously expressed. In particular, expression is high in pancreas, placenta, lung, genital tract and spleen.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis type 10	DISI9BHV	Definitive	Autosomal dominant	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Supportive	Autosomal dominant	[2]
Frontotemporal dementia with motor neuron disease	DISPZM6A	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of TAR DNA-binding protein 43 (TARDBP).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of TAR DNA-binding protein 43 (TARDBP).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of TAR DNA-binding protein 43 (TARDBP).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[10]
Hydroquinone	DM6AVR4	Approved	Hydroquinone affects the expression of TAR DNA-binding protein 43 (TARDBP).	[11]
Doxycycline	DM7ICNU	Approved	Doxycycline decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[13]
Hexachlorophene	DMLKSE0	Approved	Hexachlorophene decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[15]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[20]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of TAR DNA-binding protein 43 (TARDBP).	[21]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[22]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[23]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[24]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the expression of TAR DNA-binding protein 43 (TARDBP).	[25]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Sorbitol	DMAN0DE	Approved	Sorbitol increases the ubiquitination of TAR DNA-binding protein 43 (TARDBP).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of TAR DNA-binding protein 43 (TARDBP).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of TAR DNA-binding protein 43 (TARDBP).	[19]
MG-132	DMKA2YS	Preclinical	MG-132 increases the ubiquitination of TAR DNA-binding protein 43 (TARDBP).	[12]

References

• [1] 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.
• [2] Amyotrophic lateral sclerosis: an update on recent genetic insights. J Neurol. 2013 Nov;260(11):2917-27. doi: 10.1007/s00415-013-7112-y. Epub 2013 Oct 2.
• [3] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Proteomics investigations of drug-induced hepatotoxicity in HepG2 cells. Toxicol Sci. 2011 Mar;120(1):109-22.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [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] 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.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [11] Proteomic analysis to identify the cellular responses induced by hydroquinone in human embryonic lung fibroblasts. Toxicol Mech Methods. 2006;16(1):1-6. doi: 10.1080/15376520500191797.
• [12] Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules. J Biol Chem. 2020 Jan 17;295(3):673-689. doi: 10.1074/jbc.RA119.010617. Epub 2019 Nov 28.
• [13] A high-content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity. J Biomol Screen. 2014 Jan;19(1):44-56. doi: 10.1177/1087057113501553. Epub 2013 Sep 9.
• [14] An optimized InCell Western screening technique identifies hexachlorophene as a novel potent TDP43 targeting drug. J Biotechnol. 2015 Aug 10;207:34-8. doi: 10.1016/j.jbiotec.2015.04.012. Epub 2015 May 16.
• [15] 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.
• [16] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] 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.
• [20] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [21] Inhibition of TDP-43 accumulation by bis(thiosemicarbazonato)-copper complexes. PLoS One. 2012;7(8):e42277. doi: 10.1371/journal.pone.0042277. Epub 2012 Aug 3.
• [22] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [23] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [24] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [25] Disease-associated mutations of TDP-43 promote turnover of the protein through the proteasomal pathway. Mol Neurobiol. 2014 Dec;50(3):1049-58. doi: 10.1007/s12035-014-8644-6. Epub 2014 Jan 30.